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Ali AE, Becker RC. The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease. J Thromb Thrombolysis 2024; 57:1283-1296. [PMID: 38662114 PMCID: PMC11645312 DOI: 10.1007/s11239-024-02985-0] [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] [Accepted: 04/13/2024] [Indexed: 04/26/2024]
Abstract
Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease and related conditions characterized by a heightened risk for thrombosis. Acute coronary syndrome, chronic coronary syndrome, ischemic stroke, and atrial fibrillation are the most common. In addition to their proclivity for thrombosis, each of these four conditions is also characterized by local and systemic inflammation, endothelial/endocardial injury and dysfunction, oxidative stress, impaired tissue-level reparative capabilities, and immune dysregulation that plays a critical role in linking molecular events, environmental triggers, and phenotypic expressions. Knowing that cardiovascular disease and thrombosis are complex and dynamic, can the scientific community identify a common pathway or specific point of interface susceptible to pharmacological inhibition or alteration that is likely to be safe and effective? The contact factors of coagulation may represent the proverbial "sweet spot" and are worthy of investigation. The following review provides a summary of the fundamental biochemistry of factor XI, its biological activity in thrombosis, inflammation, and angiogenesis, new targeting drugs, and a pragmatic approach to managing hemostatic requirements in clinical trials and possibly day-to-day patient care in the future.
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Affiliation(s)
- Ahmed E Ali
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Richard C Becker
- Department of Internal Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
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Barg AA, Livnat T, Kenet G. Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment. Blood 2024; 143:1455-1464. [PMID: 38194679 DOI: 10.1182/blood.2023020721] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/22/2023] [Accepted: 12/29/2023] [Indexed: 01/11/2024] Open
Abstract
ABSTRACT Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.
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Affiliation(s)
- Assaf Arie Barg
- National Hemophilia Center, Coagulation Unit and Amalia Biron Research Institution of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tami Livnat
- National Hemophilia Center, Coagulation Unit and Amalia Biron Research Institution of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gili Kenet
- National Hemophilia Center, Coagulation Unit and Amalia Biron Research Institution of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Martínez-Carballeira D, Caro A, Bernardo Á, Corte JR, Iglesias JC, Hernández de Castro IA, Gutiérrez L, Soto I. Rare bleeding disorders: Real-world data from a Spanish tertiary hospital. Blood Cells Mol Dis 2024; 106:102837. [PMID: 38387429 DOI: 10.1016/j.bcmd.2024.102837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/14/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
INTRODUCTION Due to their low prevalence, rare bleeding disorders (RBDs) remain poorly characterized. AIM To gain insight of RBDs through our clinical practice. METHODS Retrospective study of the medical records of RBD patients followed up at the Central University Hospital of Asturias between January 2019 and December 2022. RESULTS A total of 149 patients were included. Factor (F) VII (44 %) and FXI (40 %) deficiencies were the most common diagnosed coagulopathies. Most of the patients were asymptomatic (60.4 %) and the most frequent type of bleeding were mucocutaneous and after surgery. All replacement treatments were administered on demand and no patient was on a prophylaxis regimen. Currently available products were safe; allergic reactions after administration of plasma were the most frequent complication. Genetic analysis, carried out on 55 patients (37 %), showed that the most frequent mutations in RBDs are of missense type (71.9 %). We identified 11 different novel genetic alterations in affected genes. The c.802C > T (p.Arg268Cys) variant, previously described, was identified in 71 % (15 of 21) of the patients with FXI deficiency genotyped and none were related (probable founder effect). CONCLUSION Our study on an unusual large single center cohort of RBD patients portrays location-dependent distinct genetic drives and clinical practice particularities.
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Affiliation(s)
- Daniel Martínez-Carballeira
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain; Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain.
| | - Alberto Caro
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain; Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Ángel Bernardo
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain; Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - José Ramón Corte
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - José Carlos Iglesias
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | | | - Laura Gutiérrez
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain; Department of Medicine, University of Oviedo, 33006 Oviedo, Spain
| | - Inmaculada Soto
- Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain; Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
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Vedovati MC, Becattini C, Agnelli G. A new strategy for anticoagulation: The factor XI inhibitors. Eur J Intern Med 2023; 116:8-15. [PMID: 37544845 DOI: 10.1016/j.ejim.2023.08.001] [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: 07/02/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/08/2023]
Abstract
Direct oral anticoagulants (DOACs) are currently the first-choice therapy for the prevention of cardioembolic events in patients with atrial fibrillation and for the treatment of venous thromboembolism (VTE) due to their more favorable efficacy to safety profile in comparison to vitamin K antagonists (VKA). DOACs did not show a clinical benefit when used for in stroke prevention in patients with mechanic or rheumatic valves or in those who underwent transcatheter aortic valve implantation (TAVI), in the treatment of VTE in patients with antiphospholipid antibody syndrome and in prevention of VTE in medically ill patients. There are some concerns for bleeding excess at the gastrointestinal site for some, but not all, DOACs. In recent years, in order to overcome the limitations of the available DOACs and to explore the advantages of anticoagulation in additional clinical settings, the development of factor XI and factor XII inhibitors as anticoagulant agents has been proposed. Emerging data show that factor XI has a minor role in the physiological process of hemostasis and an important role in the development of thrombosis. Bleeding has been viewed for several years as an unavoidable side effect of anticoagulant therapy. The aim of factor XI inhibitors is to challenge this dogma by favoring the uncoupling between hemostasis and thrombosis. This paper provides an update on the rationale for the use of factor XI inhibitors, their pharmacological properties and the preliminary clinical findings.
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Affiliation(s)
- Maria Cristina Vedovati
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Piazzale Giorgio Menghini, 3, Perugia 06129, Italy.
| | - Cecilia Becattini
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Piazzale Giorgio Menghini, 3, Perugia 06129, Italy
| | - Giancarlo Agnelli
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Piazzale Giorgio Menghini, 3, Perugia 06129, Italy; Maugeri Scientific Clinical Institutes - IRCCS, Pavia, Italy
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Honda S, Shimahara Y, Chikasawa Y, Ogino H. Hemostatic protocol and risk-reduction surgery for treating coronary artery disease with aortic stenosis in a patient with combined coagulation factor VIII and XI deficiency: a case report. Eur Heart J Case Rep 2023; 7:ytad219. [PMID: 37168362 PMCID: PMC10166512 DOI: 10.1093/ehjcr/ytad219] [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: 12/23/2022] [Revised: 01/25/2023] [Accepted: 04/24/2023] [Indexed: 05/13/2023]
Abstract
Background Cardiac surgery remains a significant challenge in patients with coagulation factor VIII (FVIII) deficiency, especially in those with multiple factor deficiencies. Case summary A 79-year-old man with combined FVIII and factor XI (FXI) deficiency was admitted for heart failure treatment. Transthoracic echocardiography revealed aortic stenosis (AS) with decreased left ventricular ejection fraction (LVEF) of 40%, mean aortic pressure gradient of 21 mmHg, and aortic valve area of 0.58 cm2. Coronary angiography revealed significant triple-vessel disease. The patient had multiple comorbidities, including diabetic end-stage renal disease treated with hemodialysis and liver cirrhosis (Child-Pugh score of A). Considering the high surgical risk, a two-stage treatment strategy was developed: the first with off-pump coronary artery bypass grafting (CABG), and the second with transcatheter aortic valve implantation if AS symptoms were significant after CABG. A perioperative hemostatic protocol by the author's heart team was used to appropriately replenish recombinant FVIII concentrates and fresh frozen plasma. The target preoperative and postoperative FVIII coagulation activity values were set at 80-100% and 60-80%, respectively, whereas the target perioperative FXI coagulation activity value was set at 30-45%. Off-pump CABG without aortic manipulation was completed without bleeding events. Transthoracic echocardiography conducted 20 months postoperatively revealed LVEF of 65% and mean aortic pressure gradient of 31 mmHg. The patient leads a normal life 21 months after surgery. Discussion The hemostatic protocol and risk-reduction surgery provided satisfactory surgical results in a patient with significant coronary artery disease and AS, high-surgical-risks, and combined FVIII and FXI deficiency.
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Affiliation(s)
- Sayaka Honda
- Tokyo Medical University, Department of Cardiovascular Surgery, Tokyo, Japan
| | - Yusuke Shimahara
- Tokyo Medical University, Department of Cardiovascular Surgery, Tokyo, Japan
| | - Yushi Chikasawa
- Tokyo Medical University, Department of Laboratory Medicine, Tokyo, Japan
| | - Hitoshi Ogino
- Tokyo Medical University, Department of Cardiovascular Surgery, Tokyo, Japan
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Benítez Hidalgo O, Martinez Garcia MF, Corrrales Insa I, Fernández‐Caballero M, Ramírez Orihuela L, Cortina Giner V, Comes Fernández N, Juarez Gimenez JC. VHrare study: Prevalence, clinical features and management of severe rare bleeding disorders in a large cohort. EJHAEM 2023; 4:476-482. [PMID: 37206292 PMCID: PMC10188473 DOI: 10.1002/jha2.664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 02/10/2023] [Indexed: 05/21/2023]
Abstract
INTRODUCTION Rare bleeding disorders (RBD) constitute 5% of total hereditary bleeding disorders, although the number could be higher, due to the presence of undiagnosed asymptomatic patients. The objective of this study was to analyze the prevalence and characteristics of patients with severe RBDs in our area. MATERIAL AND METHODS We analyzed the patients with RBD followed at a tertiary-level hospital between January 2014 and December 2021. RESULTS A total of 101 patients were analyzed, with a median age at diagnosis of 27.67 years (range 0-89), of which 52.47% were male. The most frequent RBD in our population was FVII deficiency. Regarding the diagnostic reason, the most frequent cause was a preoperative test and only 14.8% reported bleeding symptoms at the time of diagnosis. A genetic study was carried out in 63.36% of patients and the most frequent mutation type found was finding a missense mutation. CONCLUSIONS The distribution of RBDs in our centre is similar to the one reported in the literature. The majority of RBDs were diagnosed from a preoperative test and this allowed preventive treatment prior to invasive procedures to avoid bleeding complications. 83% of patients did not have a pathological bleeding phenotype according to ISTH-BAT.
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Affiliation(s)
- Olga Benítez Hidalgo
- Hematology DepartmentHospital Universitari Vall d'Hebron, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital CampusBarcelonaSpain
- Medicine DepartmentUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Maria Fernanda Martinez Garcia
- Hematology DepartmentHospital Universitari Vall d'Hebron, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital CampusBarcelonaSpain
- Medicine DepartmentUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Irene Corrrales Insa
- Congenital CoagulopatiesBanc de Sang i TeixitsBarcelonaSpain
- Transfusional Medicine, Vall d'Hebron Institut de RecercaUniversitat Autònoma de Barcelona (VHIR‐UAB)BarcelonaSpain
| | - Mariana Fernández‐Caballero
- Laboratory of Haematology, ICO‐Badalona, Germans Trias i Pujol University Hospital, Institut Josep Carreras Contra la LeucemiaUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Lorena Ramírez Orihuela
- Congenital CoagulopatiesBanc de Sang i TeixitsBarcelonaSpain
- Transfusional Medicine, Vall d'Hebron Institut de RecercaUniversitat Autònoma de Barcelona (VHIR‐UAB)BarcelonaSpain
| | | | - Natàlia Comes Fernández
- Congenital CoagulopatiesBanc de Sang i TeixitsBarcelonaSpain
- Transfusional Medicine, Vall d'Hebron Institut de RecercaUniversitat Autònoma de Barcelona (VHIR‐UAB)BarcelonaSpain
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Trossaert M, Chamouard V, Biron-Andreani C, Casini A, De Mazancourt P, De Raucourt E, Drillaud N, Frotscher B, Guillet B, Lebreton A, Roussel-Robert V, Rugeri L, Dargaud Y. Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders. Eur J Haematol 2023; 110:584-601. [PMID: 36748278 DOI: 10.1111/ejh.13941] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described. AIM Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.
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Affiliation(s)
- Marc Trossaert
- Haemophilia Treatment Centre, University Hospital of Nantes and French Reference Centre on Haemophilia, Nantes, France
| | - Valerie Chamouard
- Haemophilia Treatment Centre, University Hospital of Lyon and French Reference Centre on Haemophilia, Lyon, France
| | | | - Alessandro Casini
- Angiology and Haemostasis Division, Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - Philippe De Mazancourt
- Laboratory of Biochemistry and Molecular Genetics, Hospital Ambroise Paré-GHU APHP, Université Paris-Saclay, Boulogne-Billancourt, France
| | | | - Nicolas Drillaud
- Haemophilia Treatment Centre, University Hospital of Nantes and French Reference Centre on Haemophilia, Nantes, France
| | - Birgit Frotscher
- Haemophilia Treatment Centre, University Hospital of Nancy, Nancy, France
| | - Benoit Guillet
- Haemophilia Treatment Centre, University Hospital of Rennes, Rennes, France
| | - Aurelien Lebreton
- Haemophilia Treatment Centre, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Lucia Rugeri
- Haemophilia Treatment Centre, University Hospital of Lyon and French Reference Centre on Haemophilia, Lyon, France
| | - Yesim Dargaud
- Haemophilia Treatment Centre, University Hospital of Lyon and French Reference Centre on Haemophilia, Lyon, France
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López Herrero R, Sánchez Quirós B, Rodríguez Jiménez RP, Muñoz Hernández H. Epidural analgesia in a patient with factor XI deficit. REVISTA ESPANOLA DE ANESTESIOLOGIA Y REANIMACION 2023; 70:108-111. [PMID: 36813034 DOI: 10.1016/j.redare.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 09/17/2021] [Indexed: 02/22/2023]
Abstract
FXI deficiency is a rare bleeding disorder characterised by a decreased level or activity of factor. Pregnant women are at increased risk of uterine bleeding during childbirth. Neuroaxial analgesia may increase the risk of epidural hematoma in these patients. However, there is no consensus on the anaesthetic management. We present the clinical case of a 36-year-old woman with a personal history of factor XI deficiency, pregnant with 38 weeks gestation who is scheduled to perform birth induction. Pre-induction factor levels were measured. They were less than 40%, so it was decided to transfuse 20 ml/kg of fresh frozen plasma. After the transfusion it had levels greater than 40%, so epidural analgesia was performed without incident. The patient had no complications secondary to epidural analgesia or transfusion of a high volume of plasma.
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Affiliation(s)
- R López Herrero
- Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - B Sánchez Quirós
- Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - R P Rodríguez Jiménez
- Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
| | - H Muñoz Hernández
- Servicio de Anestesiología y Reanimación, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
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A Case Report of Severe Factor XI Deficiency during Cardiac Surgery: Less Can Be More. J Cardiovasc Dev Dis 2022; 9:jcdd9040118. [PMID: 35448094 PMCID: PMC9027232 DOI: 10.3390/jcdd9040118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 01/27/2023] Open
Abstract
Severe congenital Factor XI (FXI) deficiency (<20% normal activity) can be associated with significant bleeding disorders, and there has been great concern for severe bleeding following cardiac surgery requiring cardiopulmonary bypass (CPB) in this patient population. Over the past four decades remarkably different approaches to this problem have been taken, including the administration of blood volumes of fresh frozen plasma, administration of activated recombinant Factor VII, and diminutive administration of heparin. We describe a case wherein the patient was assessed in the perioperative period with a point-of-care, viscoelastic hemostasis device (ROTEM), with changes in the intrinsic/Factor XII-dependent coagulation pathway determined before, during, and after CPB. Fresh frozen plasma was administered in small amounts (5−7.5 mL/kg) just before surgery began and just before cessation of CPB. Administering fresh frozen plasma to the patient to nearly normalize in vitro ROTEM hemostasis values at times when hemostasis was needed resulted in no important bleeding occurring or need of further transfusion of other blood products. In conclusion, by using small amounts of fresh frozen plasma guided by ROTEM, an evidenced-based, precision medicine approach resulted in optimized patient care and outcome.
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022. [DOI: 10.12998/wjcc.v10.i9.2698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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11
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022; 10:2700-2709. [PMID: 35434115 PMCID: PMC8968801 DOI: 10.12998/wjcc.v10.i9.2700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/29/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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12
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Désage S, Dargaud Y, Meunier S, Le Quellec S, Lienhart A, Negrier C, Nougier C, Rugeri L. Report of surgeries, their outcome and the thrombin generation assay in patients with Factor XI deficiency: A retrospective single-centre study. Haemophilia 2022; 28:301-307. [PMID: 35122661 DOI: 10.1111/hae.14506] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 01/12/2022] [Accepted: 01/26/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND In patients with FXI deficiency, the risk of surgery-related bleeding is poorly correlated with plasma FXI activity (FXI:C); the latter can therefore not be used as a reliable predictor of bleeding in surgeries. OBJECTIVES The aim of this retrospective study was to determine whether thrombin generation assay (TGA) could be used to evaluate the risk of surgery-related bleeding in FXI-deficient patients. TGA parameters were compared to FXI:C values, haemostatic treatments and surgical outcomes. PATIENTS All patients followed at the haemophilia treatment care centre (Lyon, France) with a FXI:C < 50IU/dL, and for whom a baseline TGA was performed between January 2014 and December 2019, were included. RESULTS Among the 175 surgeries reported herein in 49 patients, FXI concentrates were used for 11 (6%) surgeries and fresh frozen plasma was used for five (3%) surgeries; these surgeries were performed in patients with two or three impaired TGA parameters. No haemostatic treatment was prescribed for 119 (68%) surgeries. A surgery-related bleeding occurred in 12 patients during 21 (12%) surgeries. Thrombin generation was significantly reduced or delayed in patients who reported surgery related-bleeding. Among the 34 (68%) surgeries performed without haemostatic treatment in patients with three impaired TGA parameters, a surgery-related bleeding was reported in 44% of cases (15 surgeries out of 34). CONCLUSION The present study confirmed that TGA is an interesting laboratory test in FXI deficiency, for determining the bleeding risk and guiding the haemostatic management of surgeries, while taking into account the surgical bleeding risk and the history of bleeding.
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Affiliation(s)
- Stéphanie Désage
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France.,Laboratoire d'hémostase, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
| | - Yesim Dargaud
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France.,Laboratoire d'hémostase, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Sandrine Meunier
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France
| | - Sandra Le Quellec
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France.,Laboratoire d'hémostase, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Anne Lienhart
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France
| | - Claude Negrier
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France.,Laboratoire d'hémostase, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Christophe Nougier
- Laboratoire d'hémostase, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
| | - Lucia Rugeri
- Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Bron, France
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13
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Abstract
Factor XI (FXI) deficiency (hemophilia C or Rosenthal disease) was first described in the 1950s in a multigenerational family experiencing bleeding related to surgery and dental procedures. Managing patients with FXI deficiency presents several challenges, including a lack of correlation of bleeding symptoms with FXI activity levels, the large volume of fresh frozen plasma required to achieve hemostatic FXI levels, lack of availability of FXI concentrate in certain regions of the world, and the inherent thrombotic risk associated with replacement therapy. This article summarizes presentation, diagnosis, and management of patients with FXI deficiency in a variety of clinical settings.
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Affiliation(s)
| | - Jean Marie Connors
- Hematology Division, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis Street, Boston, MA 02215, USA. https://twitter.com/connors_md
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14
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Bertaggia Calderara D, Zermatten MG, Aliotta A, Batista Mesquita Sauvage AP, Carle V, Heinis C, Alberio L. Tissue Factor-Independent Coagulation Correlates with Clinical Phenotype in Factor XI Deficiency and Replacement Therapy. Thromb Haemost 2020; 121:150-163. [PMID: 32920807 DOI: 10.1055/s-0040-1715899] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND In factor XI (FXI) deficiency, bleeding cannot be predicted by routine analyses. Since FXI is involved in tissue factor (TF)-independent propagation loop of coagulation, we hypothesized that investigating the spatiotemporal separated phases of coagulation (TF-dependent and -independent) could improve diagnostics. OBJECTIVES This article investigates the correlation of parameters describing TF-dependent and -independent coagulation with the clinical phenotype of FXI deficiency and their ability to assess hemostasis after FXI replacement. METHODS We analyzed: (1) plasma from healthy controls (n = 53); (2) normal plasma (n = 4) spiked with increasing concentrations of a specific FXI inhibitor (C7P); (3) plasma from FXI-deficient patients (n = 24) with different clinical phenotypes (13 bleeders, 8 non-bleeders, 3 prothrombotics); (4) FXI-deficient plasma spiked with FXI concentrate (n = 6); and (5) plasma from FXI-deficient patients after FXI replacement (n = 7). Thrombin generation was measured with the reference method calibrated automated thrombogram and with Thrombodynamics (TD), a novel global assay differentiating TF-dependent and -independent coagulation. RESULTS C7P dose-dependently decreased FXI activity, prolonged activated partial thromboplastin time, and hampered TF-independent coagulation. In FXI-deficient bleeders, TD parameters describing TF-independent propagation of coagulation and fibrin clot formation were reduced compared with controls and FXI-deficient nonbleeders and increased in FXI-deficient patients with prothrombotic phenotype. Receiver operating characteristic analysis indicated that TF-independent parameters were useful for discriminating FXI-deficient bleeders from non-bleeders. In FXI-deficient plasma spiked with FXI concentrate and in patients receiving FXI replacement, TD parameters were shifted toward hypercoagulation already at plasma FXI levels around 20%. CONCLUSION TF-independent coagulation parameters assessed by TD have the potential to identify the clinical phenotype in FXI-deficient patients and to monitor FXI replacement therapy.
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Affiliation(s)
- Debora Bertaggia Calderara
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Maxime G Zermatten
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Alessandro Aliotta
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Ana P Batista Mesquita Sauvage
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Vanessa Carle
- Institute of Chemical Sciences and Engineering, Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Christian Heinis
- Institute of Chemical Sciences and Engineering, Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Lorenzo Alberio
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
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15
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Wheeler AP, Hemingway C, Gailani D. The clinical management of factor XI deficiency in pregnant women. Expert Rev Hematol 2020; 13:719-729. [PMID: 32437625 DOI: 10.1080/17474086.2020.1772745] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Factor XI (FXI) deficiency is associated with highly variable bleeding, including excessive gynecologic and obstetrical bleeding. Since approximately 20% of FXI-deficient women will experience pregnancy-related bleeding, careful planning and knowledge of appropriate hemostatic management is pivotal for their care. AREAS COVERED In this manuscript, authors present our current understanding of the role of FXI in hemostasis, the nature of the bleeding phenotype caused by its deficiency, and the impact of deficiency on obstetrical care. The authors searched PubMed with the terms, 'factor XI', 'factor XI deficiency', 'women', 'pregnancy', and 'obstetrics' to identify literature on these topics. Expectations of pregnancy-related complications in women with FXI deficiency, including antepartum, abortion-related, and postpartum bleeding, as well as bleeding associated with regional anesthesia are discussed. Recommendations for the care of these women are considered, including guidance for management of prophylactic care and acute bleeding. EXPERT COMMENTARY FXI deficiency results in a bleeding diathesis in some, but not all, patients, making treatment decisions and clinical management challenging. Currently available laboratory assays are not particularly useful for distinguishing patients with FXI deficiency who are prone to bleeding from those who are not. There is a need for alternative testing strategies to address this limitation.
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Affiliation(s)
- Allison P Wheeler
- Department of Pathology, Microbiology and Immunology, Vanderbilt University , Nashville, TN, USA.,Department of Pediatrics, Vanderbilt University , Nashville, TN, USA
| | - Celeste Hemingway
- Department of Obstetrics and Gynecology, Vanderbilt University , Nashville, TN, USA
| | - David Gailani
- Department of Pathology, Microbiology and Immunology, Vanderbilt University , Nashville, TN, USA
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16
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Shapiro A. The use of prophylaxis in the treatment of rare bleeding disorders. Thromb Res 2019; 196:590-602. [PMID: 31420204 DOI: 10.1016/j.thromres.2019.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 07/02/2019] [Accepted: 07/16/2019] [Indexed: 12/15/2022]
Abstract
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation factor deficiencies that include fibrinogen, prothrombin, α2-antiplasmin, plasminogen activator inhibitor-1, and factors II, V, V/VIII, VII, X, XI and XIII. The incidence varies based upon the disorder and typically ranges from 1 in 500,000 to 1 per million population. Symptoms vary with the disorder and residual level of the clotting factor, and can range from relatively minor such as epistaxis, to life threatening, such as intracranial hemorrhage. Rapid treatment of bleeding episodes in individuals with severe bleeding phenotypes is essential to preserve life or limb and to prevent long-term sequelae; therapeutic options depend on the deficiency and range from plasma-derived (eg, fresh frozen plasma, prothrombin complex concentrates, factor X concentrate) to highly purified and recombinant single factor concentrates. The rarity of these disorders limits the feasibility of conventional prospective clinical trials; instead, clinicians rely upon registries, published case reports/series and experience to guide treatment. In some disorders, long-term prophylactic therapy is administered in response to the bleeding phenotype in an individual patient or based on the known natural history and severity of the deficiency. Intermittent prophylaxis, surrounding surgery, pregnancy, labor, and menstruation may be required to prevent or control excessive bleeding. This review summarizes therapeutic options, guidelines, recommendations and observations from the published literature for long-term, surgical, gynecological, and obstetric prophylaxis in deficiencies of fibrinogen; prothrombin; factors II, V, V/VIII, VII, X, XI and XIII; combined vitamin-K dependent factors; α2-antiplasmin; and plasminogen activator inhibitor 1. Platelet disorders including Glanzmann's thrombasthenia and Bernard-Soulier syndrome are also addressed.
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Affiliation(s)
- Amy Shapiro
- Indiana Hemophilia & Thrombosis Center, 8326 Naab Rd., Indianapolis, IN 46260, USA.
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17
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Treatment of rare factor deficiencies other than hemophilia. Blood 2018; 133:415-424. [PMID: 30559262 DOI: 10.1182/blood-2018-06-820738] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/18/2018] [Indexed: 12/18/2022] Open
Abstract
The deficiency of fibrinogen, prothrombin, factor V (FV), FVII, FVIII, FIX, FX, FXI, and FXIII, called rare coagulation disorders (RCDs), may result in coagulopathies leading to spontaneous or posttrauma and postsurgery hemorrhages. RCDs are characterized by a wide variety of symptoms, from mild to severe, which can vary significantly from 1 disease to another and from 1 patient to another. The most typical symptoms of all RCDs are mucosal bleedings and bleeding at the time of invasive procedures, whereas other life-threatening symptoms such as central nervous system bleeding and hemarthroses are mostly present only in some deficiencies (afibrinogenemia, FX, and FXIII). At variance with hemophilia A and B and von Willebrand disease, RCDs are much less prevalent, ranging from 1 case in 500 000 to 1 in 2 million in the general population. Their clinical heterogeneity associated with the low number of patients has led to a delay in the development of appropriate therapies. Indeed, a similar heterogeneity can also be found in the treatment products available, ranging from the specific recombinant proteins to treat FVII- and FXIII-deficient patients to the complete absence of specific products to treat patients with FII or FV deficiencies, for whom prothrombin complex concentrates or fresh frozen plasma are, to date, the only option. The recent development of novel hemostatic approaches for hemophilia, such as the use of nonsubstitutive therapy as RNA interference, anti-tissue factor pathway inhibitor, and the gene therapy aimed at improving the patient's quality of life may also have an important role in the treatment of patients with RCDs in the future.
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18
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Gidley GN, Holle LA, Burthem J, Bolton-Maggs PHB, Lin FC, Wolberg AS. Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. Blood Adv 2018; 2:1076-1088. [PMID: 29760205 PMCID: PMC5965046 DOI: 10.1182/bloodadvances.2017015123] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 04/06/2018] [Indexed: 11/20/2022] Open
Abstract
Individuals with factor XI (FXI) deficiency have a variable bleeding risk that cannot be predicted from plasma FXI antigen or activity. This limitation can result in under- or overtreatment of patients and risk of bleeding or thrombosis. Previously, plasma clot fibrinolysis assays showed sensitivity to bleeding tendency in a small cohort of patients with severe FXI deficiency. Here, we determined the ability of plasma clot formation, structure, and fibrinolysis assays to predict bleeding tendency in a larger, independent cohort of patients with severe and partial FXI deficiency. Patients were characterized as nonbleeders or bleeders based on bleeding after tonsillectomy and/or dental extraction before diagnosis of FXI deficiency. Blood was collected in the absence or presence of the contact pathway inhibitor corn trypsin inhibitor (CTI). Clotting was triggered in platelet-poor plasma with tissue factor, CaCl2, and phospholipids in the absence and presence of thrombomodulin or tissue plasminogen activator. Clot formation and fibrinolysis were assessed by turbidity and confocal microscopy. CTI-treated plasmas from bleeders showed significantly reduced clot formation and decreased resistance to fibrinolysis compared with plasmas from controls or nonbleeders. Differences were enhanced in the presence of CTI. A model that combines activated partial thromboplastin time with the rate of clot formation and area under the curve in fibrinolysis assays identifies most FXI-deficient bleeders. These results show assays with CTI-treated platelet-poor plasma reveal clotting and clot stability deficiencies that are highly associated with bleeding tendency. Turbidity-based fibrinolysis assays may have clinical utility for predicting bleeding risk in patients with severe or partial FXI deficiency.
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Affiliation(s)
- Gillian N Gidley
- Department of Haematology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- Institute of Cancer Sciences, The University of Manchester, Manchester, United Kingdom
| | - Lori A Holle
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - John Burthem
- Department of Haematology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- Institute of Cancer Sciences, The University of Manchester, Manchester, United Kingdom
| | - Paula H B Bolton-Maggs
- Institute of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
- Serious Hazards of Transfusion Office, Manchester Blood Centre, Plymouth Grove, Manchester, United Kingdom; and
| | - Feng-Chang Lin
- Department of Biostatistics and
- North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Alisa S Wolberg
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
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19
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20
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Strauss E, Mazzeffi M, Williams B, Key N, Tanaka K. Perioperative management of rare coagulation factor deficiency states in cardiac surgery. Br J Anaesth 2017; 119:354-368. [DOI: 10.1093/bja/aex198] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2017] [Indexed: 01/21/2023] Open
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21
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Verghese L, Tingi E, Thachil J, Hay C, Byrd L. Management of parturients with Factor XI deficiency—10 year case series and review of literature. Eur J Obstet Gynecol Reprod Biol 2017. [DOI: 10.1016/j.ejogrb.2017.06.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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22
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23
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Pike GN, Cumming AM, Thachil J, Hay CRM, Bolton-Maggs PHB, Burthem J. Evaluation of the use of rotational thromboelastometry in the assessment of FXI deficency. Haemophilia 2017; 23:449-457. [DOI: 10.1111/hae.13136] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2016] [Indexed: 11/27/2022]
Affiliation(s)
- G. N. Pike
- Department of Haematology; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
- Institute of Cancer Sciences; The University of Manchester; Manchester UK
| | - A. M. Cumming
- Haematology Molecular Diagnostics Centre; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
| | - J. Thachil
- Department of Haematology; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
| | - C. R. M. Hay
- Department of Haematology; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
- Haematology Molecular Diagnostics Centre; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
| | - P. H. B. Bolton-Maggs
- The University of Manchester; Manchester UK
- SHOT Office; Manchester Blood Centre; Manchester UK
| | - J. Burthem
- Department of Haematology; Manchester Royal Infirmary; Central Manchester University Hospital NHS Trust; Manchester UK
- Institute of Cancer Sciences; The University of Manchester; Manchester UK
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24
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de Raucourt E, Bauduer F, Goudemand J. Response to Wiewel-Verschueren S et al
.: gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review. Haemophilia 2016; 22:e435-6. [DOI: 10.1111/hae.13036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2016] [Indexed: 11/27/2022]
Affiliation(s)
- E. de Raucourt
- Service d'Hématologie-Biologique; Hôpital Beaujon; HUPNVS; AP-HP; Clihy France
- U1148; INSERM; Paris France
- Centre de traitement de l'Hémophilie; Hôpital Mignot; Le Chesnay France
| | - F. Bauduer
- Clinical Haematology; Centre Hospitalier de la Côte Basque; Bayonne France
- UMR 5199 PACEA; University of Bordeaux; Pessac France
| | - J. Goudemand
- Hematology and Transfusion; Faculte de Medecine; Lille University Hospital; Lille 2 University; Lille France
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25
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Wiewel-Verschueren S, Meijer K. Gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review: response to rebuttal. Haemophilia 2016; 22:e436-7. [PMID: 27481127 DOI: 10.1111/hae.13053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2016] [Indexed: 11/27/2022]
Affiliation(s)
- S Wiewel-Verschueren
- Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, The Netherlands.,Department of Obstetrics & Gynaecology, University Medical Centre Groningen, Groningen, The Netherlands
| | - K Meijer
- Division of Haemostasis and Thrombosis, Department of Haematology, University Medical Centre Groningen, Groningen, The Netherlands.
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26
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Girolami A, Cosi E, Santarossa C, Ferrari S, Lombardi AM. Thrombotic Events in Asymptomatic FXII Deficiency versus Symptomatic FXI Deficiency: Surprising Observations. Acta Haematol 2016; 136:118-22. [PMID: 27385629 DOI: 10.1159/000445854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/29/2016] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To evaluate the impact of an asymptomatic congenital clotting defect (FXII deficiency) versus that of a similar but symptomatic defect (FXI deficiency) on protection from thrombosis. PATIENTS AND METHODS All patients with FXII or FXI deficiency and thrombosis were gathered from a time-unlimited PubMed search that was carried out twice and from personal records. Combined defects were excluded. The defect had to be proven by the demonstration of a suited hereditary pattern and by a specific clotting assay. Only patients with a factor activity level of <30% of normal were selected. RESULTS Twenty-eight patients with an FXII deficiency presented with arterial thrombosis, mainly myocardial infarction, and 29 showed venous thrombosis; for FXI deficiency, these figures were 43 and 10, respectively. The ratio of arterial and venous thrombosis was 0.96 and 4.3, respectively, for FXII and FXI deficiency. CONCLUSIONS Factor FXII deficiency supplies no protection from arterial or venous thrombosis. FXI deficiency shows no protection from arterial thrombosis but appears to guarantee protection from venous thrombosis. A symptomatic, namely bleeding, condition (FXI deficiency) provides protection from venous thrombosis whereas an asymptomatic one (FXII deficiency) does not.
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Affiliation(s)
- A Girolami
- Department of Medicine, University of Padua Medical School, Padua, Italy
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27
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28
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Girolami A, Cosi E, Tasinato V, Santarossa C, Ferrari S, Girolami B. Drug-Induced Thrombophilic or Prothrombotic States: An Underestimated Clinical Problem That Involves Both Legal and Illegal Compounds. Clin Appl Thromb Hemost 2016; 23:775-785. [DOI: 10.1177/1076029616652724] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.
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Affiliation(s)
- A. Girolami
- Division of Medicine, University of Padua Medical School, Padua, Italy
| | - E. Cosi
- Division of Medicine, University of Padua Medical School, Padua, Italy
| | - V. Tasinato
- Division of Medicine, University of Padua Medical School, Padua, Italy
| | - C. Santarossa
- Division of Medicine, University of Padua Medical School, Padua, Italy
| | - S. Ferrari
- Division of Medicine, University of Padua Medical School, Padua, Italy
| | - B. Girolami
- Division of Medicine, Padua City Hospital, Padua, Italy
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29
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Abstract
The introduction of clotting factor concentrates has transformed the lives of persons with inherited bleeding disorders. With the use of prophylactic treatment, it is now possible to prevent bleeding in these individuals. The early concentrates were contaminated with the HIV and hepatitis C viruses (HCV) and resulted in major morbidity and mortality in the recipients. Current products are much safer, especially in terms of infectious agents, but other adverse events such as alloantibodies (inhibitors), allergic reactions and thrombotic risks remain of concern. Approximately 30% of previously untreated patients with severe haemophilia A develop inhibitors, making this the most important issue in haemophilia care today. Recently, it was suggested that one of the most commonly used concentrates was associated with a higher inhibitor risk, but this was not supported by the evidence from all studies. Good safety surveillance systems are essential for all diseases and products but are particularly so in the group of individuals with inherited bleeding disorders treated with clotting factor concentrates who have suffered disproportionately from the adverse effects of their treatment. National and multinational systems are now in place to allow reporting of adverse events in patients with inherited bleeding disorders. All clinicians treating individuals with inherited bleeding disorders should prospectively report adverse events to treatment even if they are believed to be common and well recognized.
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Affiliation(s)
- R Lassila
- Helsinki University Hospital, Coagulation Disorders, Hematology and Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland
| | - M Makris
- Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield, UK.,Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
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30
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Girolami A, Peroni E, Girolami B, Ferrari S, Lombardi AM. Congenital factor XI and factor VII deficiencies assure an apparent opposite protection against arterial or venous thrombosis: An intriguing observation. ACTA ACUST UNITED AC 2016; 21:486-9. [PMID: 26872273 DOI: 10.1080/10245332.2015.1112495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To investigate the prevalence and type of thrombotic events reported in patients with congenital factor XI (FXI) or factor VII (FVII) deficiency. PATIENTS AND METHODS Data on all patients with congenital FXI or FVII deficiency and a thrombotic event were gathered by means of a time unlimited PubMed search carried out in June 2014 and in February 2015. Appropriate keywords including the medical subject headings were used in both instances. Side tables were also consulted and cross-checking of the references was carried out to avoid omissions. The thrombosis event had to be proven by objective methods. RESULTS Forty-three patients with FXI deficiency had arterial thrombosis and only eight had venous thrombosis. On the contrary, only five patients with FVII deficiency had arterial thrombosis whereas 31 patients had venous thrombosis. The arterial/venous ratios were 5.37 and 0.17 for FXI or FVII, respectively. CONCLUSIONS Arterial thrombosis is frequent in FXI deficiency whereas venous thrombosis is rare. The reverse is true for FVII deficiency. The significance of these findings is discussed especially in view of the recent use of synthetic anti-FXI compounds in the prophylaxis of post-orthopedic surgery of venous thrombosis complications.
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Affiliation(s)
- A Girolami
- a Department of Medicine , University of Padua Medical School , Italy
| | - E Peroni
- a Department of Medicine , University of Padua Medical School , Italy
| | - B Girolami
- b Division of Medicine , Padua City Hospital , Italy
| | - S Ferrari
- a Department of Medicine , University of Padua Medical School , Italy
| | - A M Lombardi
- a Department of Medicine , University of Padua Medical School , Italy
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31
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Preoperative management of factor XI deficiency with therapeutic plasma exchange: A case report and literature review. J Clin Apher 2015; 31:579-583. [DOI: 10.1002/jca.21442] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 11/24/2015] [Indexed: 11/07/2022]
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32
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Ling G, Kagdi H, Subel B, Chowdary P, Gomez K. Safety and efficacy of factor
XI
(FXI) concentrate use in patients with
FXI
deficiency: a single‐centre experience of 19 years. Haemophilia 2015; 22:411-8. [DOI: 10.1111/hae.12868] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2015] [Indexed: 11/26/2022]
Affiliation(s)
- G. Ling
- Katherine Dormandy Haemophilia and Thrombosis Centre Royal Free Hospital London UK
| | - H. Kagdi
- Katherine Dormandy Haemophilia and Thrombosis Centre Royal Free Hospital London UK
| | - B. Subel
- Katherine Dormandy Haemophilia and Thrombosis Centre Royal Free Hospital London UK
| | - P. Chowdary
- Katherine Dormandy Haemophilia and Thrombosis Centre Royal Free Hospital London UK
| | - K. Gomez
- Katherine Dormandy Haemophilia and Thrombosis Centre Royal Free Hospital London UK
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33
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Pike GN, Cumming AM, Hay CRM, Sempasa B, Sutherland M, Thachil J, Burthem J, Bolton‐Maggs PHB. In vitro
comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major
FXI
deficiency. Haemophilia 2015; 22:403-10. [DOI: 10.1111/hae.12846] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 09/20/2015] [Indexed: 11/28/2022]
Affiliation(s)
- G. N. Pike
- Department of Haematology Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
- Institute of Cancer Sciences The University of ManchesterManchester UK
| | - A. M. Cumming
- Haematology Molecular Diagnostics Centre Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
| | - C. R. M. Hay
- Department of Haematology Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
- The University of Manchester Manchester UK
| | - B. Sempasa
- Haematology Molecular Diagnostics Centre Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
| | - M. Sutherland
- Haematology Molecular Diagnostics Centre Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
| | - J. Thachil
- Department of Haematology Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
| | - J. Burthem
- Department of Haematology Manchester Royal Infirmary Central Manchester University Hospital NHS TrustManchester UK
- Institute of Cancer Sciences The University of ManchesterManchester UK
| | - P. H. B. Bolton‐Maggs
- The University of Manchester Manchester UK
- SHOT office Manchester Blood Centre Plymouth Grove Manchester UK
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34
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Casini A, de Moerloose P. Factor concentrates for rare congenital coagulation disorders: where are we now? Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2016.1108188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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35
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Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood 2015; 126:397-405. [PMID: 25911238 DOI: 10.1182/blood-2014-12-616565] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 04/22/2015] [Indexed: 11/20/2022] Open
Abstract
Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations. When contact activation was inhibited and platelets were absent, FXI:C levels did not correlate with thrombin generation parameters, and control and FXI-deficient individuals were not distinguished. In all other sample types, the best discrimination was obtained using TF 0.5 pM and assay measures: endogenous thrombin potential (ETP) and peak height. We showed that although a number of conditions could distinguish differences between the groups tested, TGA measured in PRP with CTI best differentiated between bleeders and nonbleeders. These measures provided high sensitivity and specificity (peak height receiver operating characteristic [ROC] area under the curve [AUC] = 0.9362; P < .0001) (ETP ROC AUC = 0.9362; P < .0001). We conclude that by using sample conditions directed to test specific pathways of FXI activation, the TGA can identify bleeding phenotype in FXI deficiency.
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36
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Batty P, Honke A, Bowles L, Hart DP, Pasi KJ, Uprichard J, Austin SK. Ongoing risk of thrombosis with factor XI concentrate: 5 years experience in two centres. Haemophilia 2015; 21:490-5. [DOI: 10.1111/hae.12682] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2015] [Indexed: 11/29/2022]
Affiliation(s)
- P. Batty
- St George's University Hospitals NHS Foundation Trust; London UK
- Barts and The London School of Medicine & Dentistry; The Royal London Hospital; QMUL; London UK
| | - A. Honke
- Barts and The London School of Medicine & Dentistry; The Royal London Hospital; QMUL; London UK
| | - L. Bowles
- The Royal London Hospital; Barts Health NHS Trust; London UK
| | - D. P. Hart
- Barts and The London School of Medicine & Dentistry; The Royal London Hospital; QMUL; London UK
| | - K. J. Pasi
- Barts and The London School of Medicine & Dentistry; The Royal London Hospital; QMUL; London UK
| | - J. Uprichard
- St George's University Hospitals NHS Foundation Trust; London UK
| | - S. K. Austin
- St George's University Hospitals NHS Foundation Trust; London UK
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37
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Pike GN, Bolton-Maggs PHB. Factor XI-related thrombosis and the role of concentrate treatment in factor XI deficiency. Haemophilia 2015; 21:477-80. [PMID: 25855096 DOI: 10.1111/hae.12678] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2015] [Indexed: 11/30/2022]
Affiliation(s)
- G N Pike
- Department of Clinical Haematology, Manchester Royal Infirmary, Manchester, UK
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38
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Bauduer F, de Raucourt E, Boyer-Neumann C, Trossaert M, Beurrier P, Faradji A, Peynet J, Borg JY, Chamouni P, Chatelanaz C, Henriet C, Bridey F, Goudemand J. Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study. Haemophilia 2015; 21:481-9. [PMID: 25817556 PMCID: PMC4657494 DOI: 10.1111/hae.12655] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 11/28/2022]
Abstract
Factor XI (FXI)-deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high-risk situations, especially when FXI levels are below 20 IU dL(-1) . HEMOLEVEN is a human plasma-derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI-deficient patients in 13 French centres in a 3-year postmarketing study. Forty-four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months-91 years). Basal FXI levels were <1 to 51 IU dL(-1) (median: 5.5); 29 patients were severely FXI-deficient (<20 IU dL(-1) ). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.
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Affiliation(s)
- F Bauduer
- Clinical Haematology, Centre Hospitalier de la Côte Basque, Bayonne and Laboratory MRGM, University of Bordeaux, Bordeaux, France
| | - E de Raucourt
- Haemophilia Treatment Center, CH Le Chesnay, Le Chesnay, France
| | - C Boyer-Neumann
- Haematology Department, CHU Antoine Beclère, Clamart, France
| | - M Trossaert
- Haematology Department, CHU Nantes, Nantes, France
| | - P Beurrier
- Haemophilia Treatment Center, CHU Angers, Angers, France
| | - A Faradji
- Haemophilia Treatment Center, Haematology Department, Hautepierre Hospital, Strasbourg, France
| | - J Peynet
- Haemophilia Treatment Center, CH Le Chesnay, Le Chesnay, France
| | - J-Y Borg
- Haemostasis Unit-CRTH, CHRU Hôpital Charles Nicolle, Rouen, France
| | - P Chamouni
- Haemostasis Unit-CRTH, CHRU Hôpital Charles Nicolle, Rouen, France
| | - C Chatelanaz
- Laboratoire français du Fractionnement et des Biotechnologies (LFB), Les Ulis, France
| | - C Henriet
- Laboratoire français du Fractionnement et des Biotechnologies (LFB), Les Ulis, France
| | - F Bridey
- Laboratoire français du Fractionnement et des Biotechnologies (LFB), Les Ulis, France
| | - J Goudemand
- Hematology and Transfusion, Faculté de Médecine, Lille University Hospital, Lille 2 University, Lille, France
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39
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Mumford AD, Ackroyd S, Alikhan R, Bowles L, Chowdary P, Grainger J, Mainwaring J, Mathias M, O'Connell N. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167:304-26. [PMID: 25100430 DOI: 10.1111/bjh.13058] [Citation(s) in RCA: 227] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Andrew D Mumford
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
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