|
1
|
Rafique S, Deeb Y, Ghanem F, Bhattarai M. Thrombotic Thrombocytopenic Purpura-Induced Cardiomyopathy and Troponin Clearance with Plasmapheresis: True or False Reassurance? Hosp Pharm 2025:00185787251328593. [PMID: 40125486 PMCID: PMC11926812 DOI: 10.1177/00185787251328593] [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: 03/25/2025]
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic hemolytic anemia caused by a deficiency in the von Willebrand factor-cleaving protease ADAMTS13, resulting in the formation of microthrombi. TTP is associated with severe cardiovascular complications, such as myocardial infarction, congestive heart failure, arrhythmias, and cardiogenic shock, which can lead to a poor prognosis. Although plasmapheresis is the cornerstone of TTP treatment, it complicates the interpretation of cardiac biomarkers due to the rapid clearance of these markers from the bloodstream. We present the case of a 19-year-old African American female diagnosed with TTP who had critically elevated levels of high-sensitivity troponin (HS troponin). Notably, her HS troponin levels declined rapidly with ongoing plasmapheresis, underscoring the difficulties in interpreting cardiac biomarkers in TTP and the effects of treatment on these values. This case highlights the challenges in diagnosing and managing cardiovascular complications associated with TTP and their impact on patient prognosis.
Collapse
Affiliation(s)
- Soomal Rafique
- Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Yara Deeb
- Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Fares Ghanem
- Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Mukul Bhattarai
- Southern Illinois University School of Medicine, Springfield, IL, USA
| |
Collapse
|
|
2
|
Fianchi L, Bonanni M, Borchiellini A, Valeri F, Giuffrida G, Grasso S, Fozza C, Ponta M, Tiscia GL, Grandone E, Vianelli N, Dedola A, Pirozzi T, Sacco M, Lancellotti S, De Cristofaro R. Real-World Data on Effectiveness and Safety of First-Line Use of Caplacizumab in Italian Centers for the Treatment of Thrombotic Thrombocytopenic Purpura: The Roscapli Study. J Clin Med 2024; 13:6561. [PMID: 39518700 PMCID: PMC11546578 DOI: 10.3390/jcm13216561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/04/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by the formation of anti-ADAMTS13 antibodies. Caplacizumab is approved for the treatment of acute episodes of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. Real-world data for the use of caplacizumab in Italy have been recently published by a limited number of centers located in the northern and middle regions of the country only. Methods: A total of 38 patients with iTTP were enrolled in the study in six Italian centers spread over the entire territory of the country. The patients' data were registered in eCRF. Results: All patients achieved normalization of platelet count (median 2.0 days, IQR: 2-4), within a time significantly shorter than in the absence of caplacizumab, as previously reported in other studies. As to the secondary aims, patients treated with caplacizumab had a few exacerbations (4/38 (10.5%)) and relapses (2/38, 5.3%). No deaths or refractoriness were observed in these patients. The total length of hospitalization was 12 days (IQR: 9-18) and only one patient required 2 days of stay in the intensive care unit. Interestingly, when caplacizumab was initiated within the first 3 days, the plasma exchange (PEX) duration was 9 days (IQR: 8-10), which was significantly lower than those reported in previous studies conducted in the absence of caplacizumab. No severe adverse event was described in the caplacizumab-treated patients. Conclusions: Caplacizumab reduced exacerbations and refractoriness compared with previously reported standard-of-care regimens. When administered in association with PEX and immunosuppressive therapy, caplacizumab provided rapid normalization of platelet count, which was responsible for lower overall hospitalization time, ICU stay, lower exacerbations and relapses compared to previously reported outcomes of studies carried out without caplacizumab.
Collapse
Affiliation(s)
- Luana Fianchi
- Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, 00168 Rome, Italy
| | - Matteo Bonanni
- Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, 00168 Rome, Italy
| | - Alessandra Borchiellini
- Regional Reference Center for Thrombotic and Haemorrhagic Disorders of Hematology, Division Department of Hematology and Oncology, A.O.U. Città della Salute e della Scienza di Torino, 10126 Torino, Italy; (A.B.)
| | - Federica Valeri
- Regional Reference Center for Thrombotic and Haemorrhagic Disorders of Hematology, Division Department of Hematology and Oncology, A.O.U. Città della Salute e della Scienza di Torino, 10126 Torino, Italy; (A.B.)
| | - Gaetano Giuffrida
- UOS e Centro di Riferimento Regionale di Malattie Ematologiche Rare, Division of Haematology, A.O.U Policlinico-S. Marco, 95123 Catania, Italy
| | - Stephanie Grasso
- UOS e Centro di Riferimento Regionale di Malattie Ematologiche Rare, Division of Haematology, A.O.U Policlinico-S. Marco, 95123 Catania, Italy
| | - Claudio Fozza
- Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
| | - Michele Ponta
- Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
| | - Giovanni L. Tiscia
- Thrombosis and Hemostasis Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, and Unità di Ostetricia e Ginecologia, Università degli Studi di Foggia, 71121 Foggia, Italy (E.G.)
| | - Elvira Grandone
- Thrombosis and Hemostasis Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, and Unità di Ostetricia e Ginecologia, Università degli Studi di Foggia, 71121 Foggia, Italy (E.G.)
| | - Nicola Vianelli
- IRCCS Azienda Ospedaliero, Istituto di Ematologia “Seràgnoli”, Universitaria di Bologna, 40121 Bologna, Italy (A.D.)
| | - Alessandra Dedola
- IRCCS Azienda Ospedaliero, Istituto di Ematologia “Seràgnoli”, Universitaria di Bologna, 40121 Bologna, Italy (A.D.)
| | - Teresa Pirozzi
- Service of Haemorrhagic and Thrombotic Diseases, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, 00168 Rome, Italy
| | - Monica Sacco
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, 00168 Rome, Italy
| | - Stefano Lancellotti
- Service of Haemorrhagic and Thrombotic Diseases, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, 00168 Rome, Italy
| | - Raimondo De Cristofaro
- Service of Haemorrhagic and Thrombotic Diseases, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, 00168 Rome, Italy
| |
Collapse
|
|
3
|
Papakonstantinou A, Kalmoukos P, Mpalaska A, Koravou EE, Gavriilaki E. ADAMTS13 in the New Era of TTP. Int J Mol Sci 2024; 25:8137. [PMID: 39125707 PMCID: PMC11312255 DOI: 10.3390/ijms25158137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2-13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP.
Collapse
Affiliation(s)
- Anna Papakonstantinou
- Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Panagiotis Kalmoukos
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (A.M.); (E.-E.K.)
| | - Aikaterini Mpalaska
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (A.M.); (E.-E.K.)
| | - Evaggelia-Evdoxia Koravou
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (A.M.); (E.-E.K.)
| | - Eleni Gavriilaki
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (A.M.); (E.-E.K.)
| |
Collapse
|
|
4
|
Omole AE, Ali A, Ogunniyi KE, Waqar D, Tobalesi O, Rahim O, Awosika A. A Case of Thrombotic Thrombocytopenic Purpura and ST-Elevation Myocardial Infarction: An Unusual Correlation. Cureus 2023; 15:e36039. [PMID: 37056547 PMCID: PMC10088566 DOI: 10.7759/cureus.36039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2023] [Indexed: 03/14/2023] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially devastating blood disorder depicted by thrombocytopenia, fever, widespread small vessel hemolytic anemia, and neurological symptoms. The involvement of the renal and neurological systems is frequently reported in TTP; however, TTP-induced acute coronary syndrome is not widely reported. We describe a case of myocardial infarction induced by TTP in a patient who presented with the typical manifestation of acute coronary syndrome. Echocardiogram revealed a myocardial injury, and detailed investigations revealed increased levels of troponin I, lactate dehydrogenase, diminished levels of haptoglobin and von Willebrand factor-cleaving protease, and schistocytes on peripheral smear, suggestive of TTP-induced myocardial infarction. His condition was stabilized after commencing plasmapheresis, steroids, and rituximab. The initial steps in the management of this patient involve the prompt administration of steroids and the urgent start of plasmapheresis to increase platelet count.
Collapse
|
|
5
|
Khalil F, Ali M, Ellithi M. Impact of Acute Coronary Syndrome on Clinical Outcomes in Patients With Thrombotic Thrombocytopenic Purpura. Cureus 2023; 15:e35878. [PMID: 37033586 PMCID: PMC10079805 DOI: 10.7759/cureus.35878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2023] [Indexed: 03/09/2023] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening clinical syndrome characterized by microangiopathy and a variable degree of end-organ ischemic damage. Cardiac involvement has been recognized as a major cause of mortality in these patients. In this study, we queried the National Inpatient Sample (NIS) for all patients hospitalized with thrombotic microangiopathy from 2002 to 2017, who also received plasma exchange (PLEX) during the same admission. A total of 6,214 patients with TTP were identified. We stratified patients based on whether or not they had acute coronary syndrome (ACS) during admission. ACS was documented in 6.3% of patients. Compared with patients without ACS, those with ACS were relatively older (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.03) and had a relatively higher prevalence of heart failure (OR, 2.02; 95% CI, 1.53-2.67) and coronary artery disease (OR, 2.69; 95% CI, 2.03-3.57). Certain complications were more prevalent in the ACS group including acute cerebrovascular accident (OR, 3.33; 95% CI, 2.94-3.78), acute heart failure (OR, 1.91; 95% CI, 1.67-2.19), acute kidney injury (OR, 1.76; 95% CI, 1.59-1.95), cardiogenic shock (OR, 2.15; 95% CI, 1.72-2.69), and respiratory failure (OR, 1.48; 95% CI, 1.32-1.66). Despite wider utilization of therapeutic plasmapheresis and improved supportive management of patients with TTP, associated morbidity and mortality remain significant. We demonstrate from this large retrospective cohort that ACS is an independent predictor of higher morbidity and mortality in TTP patients.
Collapse
|
|
6
|
Ventricular Tachycardia in a Pediatric Patient with High-Risk Thrombotic Thrombocytopenia Purpura. Case Rep Cardiol 2023; 2023:6466680. [PMID: 36713822 PMCID: PMC9876691 DOI: 10.1155/2023/6466680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/13/2022] [Accepted: 12/27/2022] [Indexed: 01/20/2023] Open
Abstract
An 8-year-old previously healthy male was diagnosed with thrombotic thrombocytopenic purpura (TTP) and increased serum cardiac troponin I. Telemetry recorded non-sustained ventricular tachycardia, without ST-segment changes or other abnormalities on serial electrocardiogram. This case illustrates that cardiac monitoring by telemetry should be considered in high-risk TTP with elevated cardiac troponin.
Collapse
|
|
7
|
Gheith Z, Kilani A, Al-Taweel O. Unusual Presentation of Thrombotic Thrombocytopenic Purpura With Non-ST-Elevation Myocardial Infarction. Cureus 2022; 14:e29499. [DOI: 10.7759/cureus.29499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2022] [Indexed: 11/05/2022] Open
|
|
8
|
Ghodsi S, Jenab Y, Mohebi M, Kamranzadeh H, Mohammadi Z. ST-Segment-Elevation Myocardial Infarction Unmasking Underlying Systemic Lupus Erythematosus or Representing Thrombotic Thrombocytopenic Purpura? Report of a Challenging Case. J Tehran Heart Cent 2022; 16:84-88. [PMID: 35082877 PMCID: PMC8742866 DOI: 10.18502/jthc.v16i2.7391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 03/24/2021] [Indexed: 11/24/2022] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder that frequently manifests itself with renal and neurological involvements. Cardiac involvement, however, has been rarely reported. In this report, we present a rare case of acquired TTP with acute myocardial infarction (AMI) as the initial manifestation. Although AMI was successfully managed by percutaneous coronary intervention, the patient developed hemolytic anemia, fever, marked thrombocytopenia, oliguria, and renal dysfunction, requiring treatment with plasma exchange and corticosteroids. TTP, albeit extremely rare, should be considered in cases with unexpected thrombocytopenia during acute-phase treatment for AMI as it can be highly lethal if not treated immediately.
Collapse
Affiliation(s)
- Saeed Ghodsi
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Yaser Jenab
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Mohebi
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hosein Kamranzadeh
- Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Zohre Mohammadi
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
Șalaru DL, Adam CA, Marcu DTM, Șimon IV, Macovei L, Ambrosie L, Chirita E, Sascau RA, Statescu C. Acute myocardial infarction and extensive systemic thrombosis in thrombotic thrombocytopenic purpura: A case report and review of literature. World J Clin Cases 2021; 9:8104-8113. [PMID: 34621868 PMCID: PMC8462192 DOI: 10.12998/wjcc.v9.i27.8104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/19/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by the pentad of hemolytic anemia, fever, thrombocytopenia, renal failure, and neurological dysfunction. The formation of microthrombi in the arterioles and capillaries of various organs is one of the main pathophysiological mechanisms. Clinical manifestations of cardiac involvement in TTP patients are variable. Acute myocardial infarction has been reported as a complication with TTP as the secondary thrombotic event. Its emergence as the initial thrombotic event is extremely rare. CASE SUMMARY A 49-year-old previously healthy man was admitted for fever, typical angina chest pain 3 d prior to presentation, and newly onset left lower limb pain. The electrocardiogram illustrated ST-elevation acute myocardial infarction of the antero-lateral wall of the left ventricle. Transthoracic echocardiography depicted two large thrombi at the apex of the left ventricle and moderately reduced ejection fraction (40%). Venous Doppler ultrasound showed occlusion of the left popliteal artery. Laboratory tests showed severe thrombocytopenia, mild hemolytic anemia, elevated D-dimers, and high troponin and creatine kinase-MB. Abdominal computed tomography revealed other thrombotic sites (superior mesenteric artery, posterior aortic wall, spleen and renal infarction, and ileum necrosis). He was immediately started on steroids and addressed to surgery for acute abdominal pain. After an initial stabilization of the hematological deficit, he went into general surgery for resection of the necrotic ileum but died soon after the intervention due to multiple organ failure. CONCLUSION Cardiac involvement in TTP patients is common, challenging and more often fatal, especially when other thrombotic complications coexist.
Collapse
Affiliation(s)
- Delia Lidia Șalaru
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
- Internal Medicine, University of Medicine and Pharmacy, ”Grigore T. Popa Iași, Romania,” Iasi 700115, Romania
| | - Cristina Andreea Adam
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
| | - Dragos Traian Marius Marcu
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
- Internal Medicine, University of Medicine and Pharmacy, ”Grigore T. Popa Iași, Romania,” Iasi 700115, Romania
| | | | - Liviu Macovei
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
- Internal Medicine, University of Medicine and Pharmacy, ”Grigore T. Popa Iași, Romania,” Iasi 700115, Romania
| | - Lucian Ambrosie
- General Surgery, ”Sf. Spiridon” Emergency Hospital Iasi, Iasi 700111, Romania
| | - Elena Chirita
- General Surgery, ”Sf. Spiridon” Emergency Hospital Iasi, Iasi 700111, Romania
| | - Radu Andy Sascau
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
- Internal Medicine, University of Medicine and Pharmacy, ”Grigore T. Popa Iași, Romania,” Iasi 700115, Romania
| | - Cristian Statescu
- Department of Cardiology, Institute of Cardiovascular Diseases, “Prof. Dr. George I.M. Georgescu,” Iasi 700503, Romania
- Internal Medicine, University of Medicine and Pharmacy, ”Grigore T. Popa Iași, Romania,” Iasi 700115, Romania
| |
Collapse
|
|
10
|
Zheng XL. The standard of care for immune thrombotic thrombocytopenic purpura today. J Thromb Haemost 2021; 19:1864-1871. [PMID: 34060225 PMCID: PMC8324529 DOI: 10.1111/jth.15406] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/30/2021] [Accepted: 05/20/2021] [Indexed: 12/20/2022]
Abstract
Targeted therapy of immune thrombotic thrombocytopenic purpura (iTTP) requires acurate and prompt diagnosis and differentiation from complement-mediated hemolytic uremic syndrome and other causes of thrombotic microangiopathy. ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin-1 Domain, member 13) evaluation (activity and inhibitors or anti-ADAMTS-13 IgG) is the key for diagnosis and further management of patients with suspected iTTP during acute episode and in clinical response or remission. Clinical trial results and real-world data have demonstrated the efficacy and safety of the triple therapy consisting of therapeutic plasma exchange, caplacizumab, and immunosuppressives (e.g., corticosteroids and rituximab) for acute iTTP. Such a therapeutic strategy has significantly accelerated the normalization of platelet counts, decreased the length of stays in the intensive care unit and the hospital, but most importantly reduced the mortality rate. The present review highlights some of the important advancements for the diagnosis and management of iTTP and proposes triple therapy as the standard of care for acute iTTP today.
Collapse
Affiliation(s)
- X Long Zheng
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
11
|
Balasubramaniyam N, Yandrapalli S, Kolte D, Pemmasani G, Janakiram M, Frishman WH. Cardiovascular Complications and Their Association With Mortality in Patients With Thrombotic Thrombocytopenic Purpura. Am J Med 2021; 134:e89-e97. [PMID: 32687814 DOI: 10.1016/j.amjmed.2020.06.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Despite widespread availability of plasmapheresis, the mortality in thrombotic thrombocytopenic purpura remains high. Cardiovascular complications have been reported as an important cause of morbidity in these patients. The burden and prognostic implications of these complications have not been well studied. We analyzed the rates of cardiovascular complications in thrombotic thrombocytopenic purpura, temporal trends, and studied its impact on in-hospital mortality. METHODS We analyzed the National Inpatient Sample (NIS) from January 2005 to September 2015 to identify adult patients with thrombotic thrombocytopenic purpura. This group was further refined by excluding patients who did not receive therapeutic plasmapheresis, and other conditions that can mimic thrombotic thrombocytopenic purpura. We identified the age- and sex-stratified rates of cardiac arrhythmias, cardiac conduction system disorders, heart failure, acute coronary syndrome, myocarditis, pericarditis, takotsubo cardiomyopathy, cardiogenic shock, cardiac arrest, and stroke. We also compared in-hospital mortality with and without cardiovascular complications. RESULTS Among 15,054 thrombotic thrombocytopenic purpura hospitalizations (mean age 46.4 years, 69% in the 18- to 54-age group, 66.2% women, and 42.9% white), a cardiovascular complication was observed in 3802 (25.3%) hospitalizations. The following cardiovascular complications were identified: stroke (10.4%), heart failure (8.3%), acute coronary syndrome (6.4%), atrial tachyarrhythmia (5.9%), ventricular tachyarrhythmia (2.0%), cardiogenic shock (0.5%), takotsubo cardiomyopathy (0.1%), atrioventricular block (0.2%), myocarditis or pericarditis (0.3), and cardiac arrest (1.9%). Rates of several cardiovascular complications were significantly higher in patients 55 years or older compared to a younger age group, whereas males had higher rates of acute coronary syndrome and tachyarrhythmias compared to females. Overall, the cardiovascular complication rate was stable during the study period. The presence of a major cardiovascular complication was associated with a significantly higher in-hospital mortality (19.7%) as compared with no major cardiovascular complication (4.1%) (adjusted odds ratio 2.09, 95% confidence interval 1.41-3.09, P <0.001). Results were generally consistent in age and sex subgroups. CONCLUSION Cardiovascular complications were frequently observed at a rate of 1 in 4 in patients hospitalized for thrombotic thrombocytopenic purpura and were associated with substantially higher in-hospital mortality. These findings underscore the need to promptly identify and treat these complications to improve outcomes.
Collapse
Affiliation(s)
| | - Srikanth Yandrapalli
- Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Dhaval Kolte
- Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | - Murali Janakiram
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
| | - William H Frishman
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
| |
Collapse
|
|
12
|
Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L, Tarawneh R, Valdes J, Peyvandi F. Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura. J Thromb Haemost 2020; 18:2503-2512. [PMID: 32914535 PMCID: PMC7880820 DOI: 10.1111/jth.15009] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its management. METHODS In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to both immune-mediated TTP (iTTP) and hereditary/congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. RESULTS The panel agreed on eleven recommendations based on evidence ranging from very low to moderate certainty. For first episode and relapses of acute iTTP, the panel made a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (TPE), and a conditional recommendation for addition of rituximab and caplacizumab. For asymptomatic iTTP with low ADAMTS13, the panel made a conditional recommendation for rituximab outside of pregnancy, and for prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, but a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. CONCLUSIONS The panel's recommendations are based on all the available evidence for the treatment effects of various approaches including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing ADAMTS13 antibody production. There was insufficient evidence for further comparison of different treatment approaches, for which future high-quality studies in iTTP (e.g., rituximab, corticosteroids, recombinant ADAMTS13, and caplacizumab) and in cTTP (eg, recombinant ADAMTS13) are needed.
Collapse
Affiliation(s)
- X. Long Zheng
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sara K. Vesely
- Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Paul Coppo
- Centre de Référence des Microangiopathies Thrombotiques, Service d’Hématologie, Hôpital Saint-Antoine, Sorbonne Université, Assistance Publique, Hôpitaux de Paris, Paris, France
| | | | - Alfonso Iorio
- Department of Health Research Methods, Research, and Impact, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | - Reem A. Mustafa
- Department of Medicine, The University of Kansas Mediccal Center, Kansas City, KS, USA
| | - Menaka Pai
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Gail Rock
- University of Ottawa, Ottawa, ON, Canada
| | - Lene Russell
- Department of Intensive Care, Copenhagen University Hospital, Copenhagen, Denmark
| | - Rawan Tarawneh
- Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
13
|
Latifi Y, Moccetti F, Wu M, Xie A, Packwood W, Qi Y, Ozawa K, Shentu W, Brown E, Shirai T, McCarty OJ, Ruggeri Z, Moslehi J, Chen J, Druker BJ, López JA, Lindner JR. Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib. Blood 2019; 133:1597-1606. [PMID: 30692122 PMCID: PMC6450432 DOI: 10.1182/blood-2018-10-881557] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/16/2019] [Indexed: 01/13/2023] Open
Abstract
The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE-/- mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE-/- mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE-/- mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.
Collapse
Affiliation(s)
| | | | - Melinda Wu
- Knight Cardiovascular Institute
- Doernbecher Children's Hospital, and
| | | | | | - Yue Qi
- Knight Cardiovascular Institute
| | | | | | | | - Toshiaki Shirai
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR
| | - Owen J McCarty
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR
| | - Zaverio Ruggeri
- Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA
| | - Javid Moslehi
- Cardiovascular Division, Vanderbilt University, Nashville, TN
| | | | - Brian J Druker
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and
| | | | - Jonathan R Lindner
- Knight Cardiovascular Institute
- Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR
| |
Collapse
|
|
14
|
Wiernek SL, Jiang B, Gustafson GM, Dai X. Cardiac implications of thrombotic thrombocytopenic purpura. World J Cardiol 2018; 10:254-266. [PMID: 30622684 PMCID: PMC6314883 DOI: 10.4330/wjc.v10.i12.254] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/20/2018] [Accepted: 11/26/2018] [Indexed: 02/06/2023] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder that essentially can affect any organ in the human body. The hallmark of the pathogenesis in TTP is the large von Willebrand factor multimers on platelet-mediated micro-thrombi formation, leading to microvascular thrombosis. Autopsy studies showed that cardiac arrest and myocardial infarction are the most common immediate causes of death in these patients. Clinical manifestations of cardiac involvement in TTP vary dramatically, from asymptomatic elevation of cardiac biomarkers, to heart failure, MI and sudden cardiac death. There is limited knowledge about optimal cardiac evaluation and management in patients with TTP. The absence of typical cardiac symptoms, combined with complicated multi-organ involvement in TTP, may contribute to the under-utilization of cardiac evaluation and treatment. Prompt diagnosis and timely initiation of effective therapy could be critically important in selected cases. Based on our experience and this review of the literature, we developed several recommendations for focused cardiac evaluation for patients with acute TTP: (1) patients with suspected or confirmed TTP should be screened for the potential presence of cardiac involvement with detailed history and physical, electrocardiogram and cardiac enzymes; (2) clinical deterioration of TTP patients warrants immediate cardiac reevaluation; (3) TTP patients with clinical evidence of cardiac involvement should be monitored for telemetry, cardiac biomarkers and evaluated with transthoracic echocardiography. These patients require urgent targeted TTP treatment as well as cardiac-specific treatment. Aspirin therapy is indicated for all TTP patients. Since epicardial coronary artery involvement is rare, cardiac catheterization is usually not required, given the high risk for hemorrhage and kidney injury; (4) we recommend evidence-based medical therapy for ischemic symptoms and heart failure. TTP patients with evidence of cardiac involvement would also benefit from routine cardiology follow up during remission.
Collapse
Affiliation(s)
- Szymon L Wiernek
- Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Bo Jiang
- Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Gregory M Gustafson
- Division of Cardiology, Lang Research Center, New York Presbyterian Medical Group – Queens Hospital, Flushing, NY 11355, United States
| | - Xuming Dai
- Division of Cardiology, Lang Research Center, New York Presbyterian Medical Group – Queens Hospital, Flushing, NY 11355, United States
| |
Collapse
|
|
15
|
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.
Collapse
Affiliation(s)
- Sumit Dahal
- Interfaith Medical Center, Brooklyn, NY, USA
| | | | | | - Suyash Dahal
- KIST Medical College and Teaching Hospital, Lalitpur, Nepal
| | | | | |
Collapse
|
|
16
|
Witsch T, Martinod K, Sorvillo N, Portier I, De Meyer SF, Wagner DD. Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice. J Am Heart Assoc 2018; 7:JAHA.117.007004. [PMID: 29367415 PMCID: PMC5850234 DOI: 10.1161/jaha.117.007004] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background A disintegrin‐like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13), the von Willebrand factor–cleaving enzyme, decreases leukocyte and platelet recruitment and, thus, reduces thrombosis and inflammation. Recombinant human ADAMTS13 (rhADAMTS13) is a novel drug candidate for ischemia/reperfusion injury and has shown short‐term benefits in mouse models of myocardial injury, but long‐term outcome has not been investigated. Methods and Results We evaluated the impact of rhADAMTS13 on cardiac remodeling, scarring, and contractile function, under chronic left ventricular pressure overload. The role of von Willebrand factor and the effect of rhADAMTS13 treatment were studied. This model of heart failure, based on ascending aortic constriction, produces a coronary inflammatory response and microvascular dysfunction, resulting in fibrotic remodeling and cardiac failure. Mice were treated with either rhADAMTS13 or vehicle and assessed for coronary vascular inflammation and ventricular function at several postsurgical time points, as well as for cardiac fibrosis after 4 weeks. Early upon induction of pressure overload under rhADAMTS13 treatment, we detected less endothelial‐lumen–associated von Willebrand factor, fewer platelet aggregates, and decreased activated transforming growth factor‐β1 levels than in vehicle‐treated mice. We observed significant preservation of cardiac function and decrease in fibrotic remodeling as a result of rhADAMTS13 administration. Conclusions Herein, we show that rhADAMTS13 decreases coronary vascular dysfunction and improves cardiac remodeling after left ventricular pressure overload in mice. We propose that this effect may, at least in part, be the result of decreased von Willebrand factor–mediated recruitment of platelets, a major source of the activated profibrotic cytokine transforming growth factor‐β1. Our study further supports the therapeutic potential of rhADAMTS13 for conditions characterized by inflammatory cardiac damage that results in fibrosis.
Collapse
Affiliation(s)
- Thilo Witsch
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.,Department of Pediatrics, Harvard Medical School, Boston, MA.,Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Kimberly Martinod
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.,Department of Pediatrics, Harvard Medical School, Boston, MA.,Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Nicoletta Sorvillo
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.,Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Irina Portier
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Simon F De Meyer
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
| | - Denisa D Wagner
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA .,Department of Pediatrics, Harvard Medical School, Boston, MA.,Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA
| |
Collapse
|
|
17
|
von Willebrand factor and its cleaving protease ADAMTS13 balance in coronary artery vessels: Lessons learned from thrombotic thrombocytopenic purpura. A narrative review. Thromb Res 2017; 155:78-85. [DOI: 10.1016/j.thromres.2017.05.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/11/2017] [Indexed: 02/08/2023]
|
|
18
|
Acute myocardial infarction as the initial thrombotic event of thrombotic thrombocytopenic purpura. Blood Coagul Fibrinolysis 2017; 27:948-951. [PMID: 26757016 DOI: 10.1097/mbc.0000000000000513] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by the coemergence of microangiopathic hemolytic anemia, thrombocytopenia, and thrombosis-mediated ischemic injuries of various organs, such as the central nervous system and kidneys. Acute myocardial infarction (AMI) has also occasionally been reported as a complication with TTP as the secondary thrombotic event; however, its emergence as the initial thrombotic event in TTP is extremely rare. This report describes an 80-year-old male patient with acquired TTP, who was affected by AMI without any clinically apparent damage to other organs or abnormal laboratory findings that would be suggestive of TTP at the first presentation. Although AMI was successfully treated by percutaneous coronary intervention (PCI), the patient developed marked thrombocytopenia with acute kidney injury and hemolytic anemia 5 days after PCI. The patient was diagnosed as having acquired TTP based on decreased ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13) below the level of detection and the presence of the inhibitor against ADAMTS13, and eventually died of multiorgan failure due to TTP despite undergoing repeated plasma exchanges and immunosuppressive therapies, including corticosteroid and rituximab. Although caution is often paid to therapy-related thrombocytopenia or renal damage after PCI, that is, those caused by antiplatelet drugs, heparin, or contrast agents, our report alerts us to the presence of TTP as an extremely rare, but underlying cause for AMI that could be subclinical at the initial presentation.
Collapse
|
|
19
|
Abstract
Thrombotic thrombocytopenia purpura (TTP) and the hemolytic uremic syndrome (HUS) are rare thrombotic microangiopathies that can be rapidly fatal. Although the acquired versions of TTP and HUS are generally highest on this broad differential, multiple rarer entities can produce a clinical picture similar to TTP/HUS, including microangiopathic hemolysis, renal failure, and neurologic compromise. More recent analysis has discovered a host of genetic factors that can produce microangiopathic hemolytic syndromes. This article discusses the current understanding of thrombotic microangiopathy and outlines the pathophysiology and causative agents associated with each distinct syndrome as well as the most accepted treatments.
Collapse
Affiliation(s)
- Joseph J Shatzel
- Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Jason A Taylor
- Division of Hematology and Medical Oncology, The Hemophilia Center, Portland VA Medical Center, Knight Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, L586, Portland, OR 97239, USA.
| |
Collapse
|
|
20
|
Acute Coronary Syndromes in Patients with Hematological Disorders. JOURNAL OF CARDIOVASCULAR EMERGENCIES 2016. [DOI: 10.1515/jce-2016-0024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Abstract
Hematological conditions can lead to serious disturbances in blood rheology, being frequently associated with increased systemic inflammation and increased risk of bleeding. The imbalance between coagulation and thrombolytic factors in patients with acute coronary syndromes may lead to undesirable outcomes, and the success of emergency coronary angioplasty or by-pass grafting may be altered by increased bleeding in coagulopathies such as hemophilia. This paper intends to review the present knowledge in the field of acute coronary syndromes in subjects with hematological and onco-hematological disorders such as thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, von Willebrand disease, hemophilia, polycythemia vera, erythrocyte disorders, myelodysplastic syndrome, leukemia, lymphoma or myeloma.
Collapse
|
|
21
|
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.
Collapse
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.
| |
Collapse
|
|
22
|
Brazelton J, Oster RA, McCleskey B, Fuller J, Adamski J, Marques MB. Increased troponin I is associated with fatal outcome in acquired thrombotic thrombocytopenic purpura. J Clin Apher 2016; 32:311-318. [DOI: 10.1002/jca.21510] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 09/07/2016] [Accepted: 09/09/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Jason Brazelton
- Department of Pathology; University of Alabama at Birmingham (UAB); Birmingham Alabama
| | - Robert A. Oster
- Department of Medicine; University of Alabama at Birmingham (UAB); Birmingham Alabama
| | - Brandi McCleskey
- Department of Pathology; University of Alabama at Birmingham (UAB); Birmingham Alabama
| | - Jessica Fuller
- Department of Pediatrics; Cincinnati Children's Hospital Medical Center; Cincinnati Ohio
| | - Jill Adamski
- Department of Laboratory Medicine and Pathology; Mayo Clinic Arizona; Phoenix Arizona
| | - Marisa B. Marques
- Department of Pathology; University of Alabama at Birmingham (UAB); Birmingham Alabama
| |
Collapse
|
|
23
|
Mouabbi JA, Zein R, Kafri Z, Al-Katib A, Hadid T. Thrombotic thrombocytopenic purpura presenting as acute coronary syndrome. Clin Case Rep 2016; 4:736-9. [PMID: 27525072 PMCID: PMC4974416 DOI: 10.1002/ccr3.606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 04/23/2016] [Accepted: 05/24/2016] [Indexed: 11/29/2022] Open
Abstract
In patients presenting with thrombotic thrombocytopenia purpura and non‐ST elevation myocardial infarction, prompt initiation of plasma exchange takes precedence over other invasive diagnostic procedures for coronary artery disease. Such procedures should be delayed until clinical condition and laboratory parameters have been stabilized.
Collapse
Affiliation(s)
- Jason Aboudi Mouabbi
- Internal Medicine St John Hospital and Medical Center Grosse Pointe Woods Michigan USA
| | - Rami Zein
- Internal Medicine St John Hospital and Medical Center Grosse Pointe Woods Michigan USA
| | - Zyad Kafri
- Van Elslander Cancer Center St John Hospital & Medical Center Grosse Pointe Woods Michigan USA
| | - Ayad Al-Katib
- Hematology Oncology St John Hospital and Medical Center Grosse Pointe Woods Michigan USA
| | - Tarik Hadid
- Van Elslander Cancer Center St John Hospital & Medical Center Grosse Pointe Woods Michigan USA
| |
Collapse
|
|
24
|
Peters A, Al Maluli H, Nayeemuddin M, Mirza A, Modi D, Arkles J, Bashir R. Thrombotic thrombocytopenia purpura: a potentially reversible cause of complete heart block. Am J Med 2015; 128:e1-3. [PMID: 26149674 DOI: 10.1016/j.amjmed.2015.05.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 05/22/2015] [Accepted: 05/22/2015] [Indexed: 11/27/2022]
Affiliation(s)
- Andrew Peters
- Department of Medicine, Temple University Hospital, Philadelphia, Pa
| | - Hayan Al Maluli
- Division of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa
| | | | - Arslan Mirza
- Department of Medicine, Temple University Hospital, Philadelphia, Pa
| | - Danesh Modi
- Division of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa
| | - Jeffrey Arkles
- Division of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa
| | - Riyaz Bashir
- Division of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa.
| |
Collapse
|
|
25
|
Tasaki T, Yamada S, Nabeshima A, Noguchi H, Nawata A, Hisaoka M, Sasaguri Y, Nakayama T. An autopsy case of myocardial infarction due to idiopathic thrombotic thrombocytopenic purpura. Diagn Pathol 2015; 10:52. [PMID: 26022055 PMCID: PMC4446843 DOI: 10.1186/s13000-015-0285-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 04/22/2015] [Indexed: 01/16/2023] Open
Abstract
UNLABELLED Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by systemic platelet-von Willebrand factor aggregation, organ ischemia and profound thrombocytopenia. In this report, we describe an autopsy case of a 77-year-old Japanese man diagnosed with idiopathic TTP. He had no history of cardiovascular disease symptoms, such as chest pain, ST segment elevation, and elevation of cardiac enzyme levels, except arrhythmia. The patient suddenly died despite receiving many treatments. On autopsy, macroscopically and microscopically, acute and chronic myocardial infarction manifested as petechiae and fibrotic foci and covered a wide area in the myocardium, including the area near the atrioventricular node. The microthrombi in the small arterioles and capillaries were platelet thrombi, which showed positive results for periodic acid-Schiff stain and factor VIII on immunohistochemical staining. The cause of the sudden death was suspected to be myocardial infarction, including a cardiac conduction system disorder due to multiple platelet microthrombi. Asymptomatic myocardial infarction is an important cause of death in TTP. Therefore, the heart tissue, including the sinus-atrial node and the atrioventricular node, should be microscopically examined more closely in autopsy cases of patients with TTP who experienced sudden death of TTP. This report is a critical teaching case considering that its cause of sudden death may be arrhythmia due to a myocardial infarction including cardiac conduction system disorder by platelet microthrombi. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2113354005156739.
Collapse
Affiliation(s)
- Takashi Tasaki
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Sohsuke Yamada
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Atsunori Nabeshima
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Hirotsugu Noguchi
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Aya Nawata
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Masanori Hisaoka
- Pathology and Oncology, University of Occupational and Environmental Health, Kitakyusyu, Japan.
| | | | - Toshiyuki Nakayama
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| |
Collapse
|
|
26
|
Sauvètre G, Grange S, Froissart A, Veyradier A, Coppo P, Benhamou Y. La révolution des anticorps monoclonaux dans la prise en charge des microangiopathies thrombotiques. Rev Med Interne 2015; 36:328-38. [DOI: 10.1016/j.revmed.2014.10.364] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 08/22/2014] [Accepted: 10/24/2014] [Indexed: 12/15/2022]
|
|
27
|
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: 102] [Impact Index Per Article: 10.2] [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.
Collapse
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
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Tuter DS, Kopylov FY, Kozlovskaya NL, Demyanova KA, Shchekochikhin DY, Shilov EM, Syrkin AL. Cardiac involvement in thrombotic microangiopathies. TERAPEVT ARKH 2015; 87:17-25. [DOI: 10.17116/terarkh201587917-25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
|
|
29
|
Alasfar S, Alachkar N. Atypical hemolytic uremic syndrome post-kidney transplantation: two case reports and review of the literature. Front Med (Lausanne) 2014; 1:52. [PMID: 25593925 PMCID: PMC4292050 DOI: 10.3389/fmed.2014.00052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 11/29/2014] [Indexed: 01/09/2023] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by over-activation and dysregulation of the alternative complement pathway. Its estimated prevalence is 1–2 per million. The disease is characterized by thrombotic microangiopathy, which causes anemia, thrombocytopenia, and acute renal failure. aHUS has more severe course compared to typical (infection-induced) HUS and is frequently characterized by relapses that leads to end stage renal disease. For a long time, kidney transplantation for these patients was contraindicated because of high rate of recurrence and subsequent renal graft loss. The post-kidney transplantation recurrence rate largely depends on the pathogenetic mechanisms involved. However, over the past several years, advancements in the understanding and therapeutics of aHUS have allowed successful kidney transplantation in these patients. Eculizumab, which is a complement C5 antibody that inhibits complement factor 5a and subsequent formation of the membrane-attack complex, has been used in prevention and treatment of post-transplant aHUS recurrence. In this paper, we present two new cases of aHUS patients who underwent successful kidney transplantation in our center with the use of prophylactic and maintenance eculizumab therapy that have not been published before. The purpose of reporting these two cases is to emphasize the importance of using eculizumab as a prophylactic therapy to prevent aHUS recurrence post-transplant in high-risk patients. We will also review the current understanding of the genetics of aHUS, the pathogenesis of its recurrence after kidney transplantation, and strategies for prevention and treatment of post-transplant aHUS recurrence.
Collapse
Affiliation(s)
- Sami Alasfar
- Department of Medicine, Division of Nephrology, The Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Nada Alachkar
- Department of Medicine, Division of Nephrology, The Johns Hopkins University School of Medicine , Baltimore, MD , USA
| |
Collapse
|
|
30
|
[Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group]. Med Clin (Barc) 2014; 144:331.e1-331.e13. [PMID: 25433791 DOI: 10.1016/j.medcli.2014.09.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/18/2014] [Indexed: 12/18/2022]
Abstract
Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients.
Collapse
|
|
31
|
Nichols L, Berg A, Rollins-Raval MA, Raval JS. Cardiac Injury Is a Common Postmortem Finding in Thrombotic Thrombocytopenic Purpura Patients: Is Empiric Cardiac Monitoring and Protection Needed? Ther Apher Dial 2014; 19:87-92. [DOI: 10.1111/1744-9987.12191] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Larry Nichols
- Department of Pathology; University of Pittsburgh Medical Center
| | - Aaron Berg
- Department of Pathology; University of Pittsburgh Medical Center
| | | | - Jay S Raval
- Department of Pathology; University of Pittsburgh Medical Center
- The Institute for Transfusion Medicine; Pittsburgh PA USA
| |
Collapse
|
|
32
|
Doll JA, Kelly JP. ST-segment elevation myocardial infarction treated with thrombolytic therapy in a patient with thrombotic thrombocytopenic purpura. J Thromb Thrombolysis 2013; 38:124-6. [DOI: 10.1007/s11239-013-1018-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
33
|
Balasubramaniyam N, Kolte D, Palaniswamy C, Yalamanchili K, Aronow WS, McClung JA, Khera S, Sule S, Peterson SJ, Frishman WH. Predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura. Am J Med 2013; 126:1016.e1-7. [PMID: 23993262 DOI: 10.1016/j.amjmed.2013.03.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 03/22/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite the widespread availability of plasmapheresis as a therapy, thrombotic thrombocytopenic purpura is associated with significant morbidity and mortality. There is a paucity of data on the predictors of poor clinical outcome in this population. Acute myocardial infarction is a recognized complication of thrombotic thrombocytopenic purpura. Little is known about the magnitude of this problem, its risk factors, and its influence on mortality in patients hospitalized with thrombotic thrombocytopenic purpura. METHODS We used the 2001-2010 Nationwide Inpatient Sample database to identify patients aged ≥18 years with the diagnosis of thrombotic thrombocytopenic purpura (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 446.6) who also received therapeutic plasmapheresis (ICD-9-CM code 99.71) during the hospitalization. Patients with acute myocardial infarction were identified using the Healthcare Cost and Utilization Project Clinical Classification Software code 100. Stepwise logistic regression was used to determine independent predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura patients. RESULTS Among the 4032 patients (mean age 47.5 years, 67.7% women, and 36.9% white) with thrombotic thrombocytopenic purpura who also underwent plasmapheresis, in-hospital mortality was 11.1%. Independent predictors of increased in-hospital mortality were older age (odds ratio [OR] 1.03; 95% confidence interval [CI], 1.02-1.04; P <.001), acute myocardial infarction (OR 1.89; 95% CI, 1.24-2.88; P = .003), acute renal failure (OR 2.75; 95% CI, 2.11-3.58; P <.001), congestive heart failure (OR 1.66; 95% CI, 1.17-2.34; P = .004), acute cerebrovascular disease (OR 2.68; 95% CI, 1.87-3.85; P <.001), cancer (OR 2.49; 95% CI, 1.83-3.40; P <.001), and sepsis (OR 2.59; 95% CI, 1.88-3.59; P <.001). Independent predictors of acute myocardial infarction were older age (OR 1.03; 95% CI, 1.02-1.04; P <.001), smoking (OR 1.60; 95% CI, 1.14-2.24; P = .007), known coronary artery disease (OR 2.59; 95% CI, 1.76-3.81; P <.001), and congestive heart failure (OR 2.40; 95% CI, 1.71-3.37; P <.001). CONCLUSION In this large national database, patients with thrombotic thrombocytopenic purpura had an in-hospital mortality rate of 11.1% and an acute myocardial infarction rate of 5.7%. Predictors of in-hospital mortality were older age, acute myocardial infarction, acute renal failure, congestive heart failure, acute cerebrovascular disease, cancer, and sepsis. Predictors of acute myocardial infarction were older age, smoking, known coronary artery disease, and congestive heart failure.
Collapse
|
|
34
|
Bennett M, Chubar Y, Gavish I, Aviv A, Stemer G, Chap-Marshak D. Experiences in a family with the Upshaw-Schulman syndrome over a 44-year period. Clin Appl Thromb Hemost 2013; 20:296-303. [PMID: 23872162 DOI: 10.1177/1076029613495309] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
A family with a novel c.717_del frameshift and a c.3655C > T missense mutation of a disintegrin and metalloproteinase with thrombospondin type I motif, member 13 protein (ADAMTS13) is described. Family members have been under observation for 44 years. Two double heterozygotes have severe early-onset Upshaw-Schulman syndrome and require prophylactic plasma infusions. Analysis reveals that 2 weekly plasma infusions are not sufficient in preventing laboratory evidence of a thrombotic thrombocytopenic purpura (TTP) attack. Both the double heterozygotes also have a heterozygous factor V Leiden G1291A mutation. One underwent splenectomy, which did not reduce the frequency of TTP episodes but resulted in a recurrent pulmonary embolism and has necessitated lifelong anticoagulant therapy. The other has mild chronic renal failure and has had episodes of atrial fibrillation and cerebral infarction. Of the 3 heterozygotes in the family, 1 has had episodes of mild thrombocytopenia.
Collapse
Affiliation(s)
- Michael Bennett
- 1Department of Haematology, The Emek Medical Centre, Afula, Israel
| | | | | | | | | | | |
Collapse
|
|
35
|
Unresponsive thrombotic thrombocytopenic purpura in critically ill adults. Intensive Care Med 2013; 39:1272-81. [PMID: 23549631 DOI: 10.1007/s00134-013-2873-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 02/04/2013] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The prognosis of thrombotic thrombocytopenic purpura (TTP) has considerably improved since the introduction of plasma exchange (PEX) therapy. However, unresponsive thrombotic thrombocytopenic purpura (Un-TTP) still carries high morbidity and mortality rates, indicating a need for early specific treatments. PATIENTS AND METHODS In a retrospective study including consecutive adults with TTP admitted between January 1997 and January 2011 in a teaching hospital intensive care unit (ICU), our objective here is to identify early clinical and laboratory features predicting Un-TTP. Patients who responded to plasma exchange and steroids (N = 49) were compared with patients with unresponsive TTP defined as requirement for other treatments, protracted course, or death (N = 37, 43 %). RESULTS Hospital mortality was 24.3 % in the Un-TTP group. Variables associated with Un-TTP on univariate logistic regression were older age, cardiac involvement, neurological involvement, higher anti-a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) immunoglobulin G (IgG) titer, lower platelet counts starting on day 2, higher Sequential Organ Failure Assessment (SOFA) scores starting on day 3, need for higher plasma volumes to obtain remission, and greater use of adjuvant treatments and life-sustaining interventions. Multivariate logistic regression identified four factors independently associated with Un-TTP: age over 60 years [odds ratio (OR) 7.90; 95 % confidence interval (95 % CI) 1.06-78.34], cardiac (OR 5.17; 95 % CI 1.63-16.39) or neurological (OR 8.04; 95 % CI 1.27-51.03) manifestations at diagnosis, and day 2 platelet count less than 15 G/l (OR 3.88; 95 % CI 1.30-11.62). CONCLUSION Therapeutic intensification starting on day 3 or even earlier in patients with the independent risk factors for unresponsive TTP identified in our study deserves evaluation in a multicenter prospective study.
Collapse
|
|
36
|
De Landtsheer Q, Labriola L, Houssiau F, Jacquet LM, Hantson P. Acute heart failure after thrombotic thrombocytopenic purpura successfully treated by ECLS. Transfus Med 2013; 23:199-201. [PMID: 23387941 DOI: 10.1111/tme.12012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/04/2012] [Accepted: 01/12/2013] [Indexed: 12/13/2022]
|
|
37
|
Atreya AR, Arora S, Sivalingam SK, Giugliano GR. ST segment elevation myocardial infarction as a presenting feature of thrombotic thrombocytopenic purpura. J Cardiovasc Dis Res 2012; 3:167-9. [PMID: 22629041 PMCID: PMC3354466 DOI: 10.4103/0975-3583.95377] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Myocardial infarction with ST segment elevation (STE) on electrocardiography (ECG) is a common presentation in emergency rooms across the world. Myocardial injury and necrosis are infrequently the initial presentation in patients with thrombotic thrombocytopenic purpura (TTP). A 48-year-old woman presented with STE myocardial infarction from outside hospital for primary percutaneous coronary intervention. However, her clinical picture was not consistent. Rapid evaluation revealed symptoms associated with microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury with waxing and waning mental status. A diagnosis of TTP was made with low ADAMST-13 activity. Plasmapheresis was initiated along with intravenous steroid therapy. The patient had a full recovery and went home after full recovery of left ventricular ejection fraction and normal myocardial perfusion studies. Rapid evaluation is needed to identify infrequent causes of STE myocardial infarction. As swift protocols are activated in the emergency room and catheterization laboratories to ensure quality control, it is equally important to integrate all aspects of the patient's clinical and objective data to detect unusual disease entities.
Collapse
Affiliation(s)
- Auras R Atreya
- Department of Internal Medicine, Baystate Medical Center/Tufts University School of Medicine, Massachusetts, USA
| | | | | | | |
Collapse
|
|
38
|
Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120:5217-23. [PMID: 22915644 DOI: 10.1182/blood-2012-06-439935] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Coronary heart disease is a major cause of death in the western world. Although essential for successful recovery, reperfusion of ischemic myocardium is inevitably associated with reperfusion injury. To investigate a potential protective role of ADAMTS13, a protease cleaving von Willebrand factor multimers, during myocardial ischemia/reperfusion, we used a mouse model of acute myocardial infarction. We found that Adamts13(-/-) mice developed larger myocardial infarctions than wild-type control mice, whereas treatment of wild-type mice with recombinant human ADAMTS13 (rhADAMTS13) led to smaller infarctions. The protective effect of ADAMTS13 was further confirmed by a significant reduction of cardiac troponin-I release and less myocardial apoptosis in mice that received rhADAMTS13 compared with controls. Platelets adherent to the blood vessel wall were observed in few areas in the heart samples from mice treated with vehicle and were not detected in samples from mice treated with rhADAMTS13. However, we observed a 9-fold reduction in number of neutrophils infiltrating ischemic myocardium in mice that were treated with rhADAMTS13, suggesting a potent anti-inflammatory effect of ADAMTS13 during heart injury. Our data show that ADAMTS13 reduces myocardial ischemia/reperfusion injury in mice and indicate that rhADAMTS13 could be of therapeutic value to limit myocardial ischemia/reperfusion injury.
Collapse
|
|
39
|
Peigne V, Perez P, Resche Rigon M, Mariotte E, Canet E, Mira JP, Coppo P, Veyradier A, Azoulay E. Causes and risk factors of death in patients with thrombotic microangiopathies. Intensive Care Med 2012; 38:1810-7. [PMID: 22797353 DOI: 10.1007/s00134-012-2638-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2012] [Accepted: 06/16/2012] [Indexed: 12/11/2022]
Abstract
PURPOSE Although plasma therapy of thrombotic micro-angiopathies (TMAs) has dramatically improved survival, the outcome remains fatal in up to 15 % of patients. We investigated the causes and risk factors of death in patients with TMA. METHODS Retrospective matched case-control national-registry study of 57 patients who died within 180 days of TMA diagnosis and 48 survivors matched on age, gender, and baseline platelet count and creatinine level. The study period was 1995-2007. Factors associated with mortality were identified using a conditional logistic regression model. RESULTS Median time from TMA symptom onset to death was 7 (5-14) days. The leading causes of death were nosocomial infections, myocardial infarction, stroke, and pulmonary embolism. Cases and controls did not differ significantly regarding haemolysis parameters, ADAMTS13 activity, or neurological or gastrointestinal involvement. TMA was more frequently related to HIV or cancer in patients who died. Compared to survivors, non-survivors more often had cardiac involvement at diagnosis (38 vs. 6 %, p = 0.03) and less often received plasma exchange therapy (60 vs. 92 %, p = 0.004). Only two factors were independently associated with mortality by multivariate analysis: cardiac involvement at diagnosis (odds ratio, 5.96; 95 % confidence interval, 1.06-33.4) and plasma exchange therapy (odds ratio, 0.25; 95 % confidence interval, 0.06-0.99). CONCLUSION Our data emphasise the adverse prognostic significance of cardiac abnormalities and support routine plasma exchange in patients with TMA. Given the high risk of cardiac and neurological complications, adequate monitoring should be proposed to these patients in appropriate hospital settings.
Collapse
Affiliation(s)
- Vincent Peigne
- AP-HP, Hôpital Saint-Louis Medical ICU, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Xu W, Wang TY, Becker RC. Enfermedades hematológicas: desde dentro del corazón. Rev Esp Cardiol 2011; 64:606-13. [DOI: 10.1016/j.recesp.2011.02.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Accepted: 02/22/2011] [Indexed: 10/18/2022]
|