Three-factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis.
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2019-05
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BACKGROUND/OBJECTIVES:Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications. MATERIALS/METHODS:After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine® ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing. RESULTS:Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P < 0·001). The mean PCC dose was 15·8 ± 7·1 IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%. CONCLUSIONS:3F-PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications.
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Hashmi, Nazish K, Kamrouz Ghadimi, Amudan J Srinivasan, Yi-Ju Li, Robert D Raiff, Jeffrey G Gaca, Adam G Root, Yaron D Barac, et al. (2019). Three-factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis. Vox sanguinis, 114(4). pp. 374–385. 10.1111/vox.12774 Retrieved from https://hdl.handle.net/10161/29728.
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Scholars@Duke
Nazish Khalid Hashmi
Kamrouz Ghadimi
Dr. Kamrouz (Kam) Ghadimi is an experienced cardiovascular acute care specialist (cardiovascular anesthesiology and intensive care), established investigator, physician leader, and associate professor of Anesthesiology and Critical Care at Duke Health.
His clinical practice is rooted in the cardiothoracic surgical ICU and operating rooms. He has broad expertise in all topics involving perioperative cardiovascular medicine and intensive care, including the management of acutely ill patients after surgery or those receiving extracorporeal life support (ECLS/ECMO). His specific area of expertise focuses on the enhancement of blood circulation through the lungs and the reversal of bleeding with prevention of thrombosis after surgery and circulatory life support. He has published original research, invited reviews, and guidance documents in several high-impact multidisciplinary journals and networks, including JAMA, Circulation, BMJ, Journal of the American College of Cardiology, Journal of Heart and Lung Transplantation, and Journal of Thrombosis & Haemostasis. He has also published in anesthesiology specialty journals, including Anesthesia & Analgesia, Anesthesiology, Current Opinion in Anesthesiology, and the British Journal of Anaesthesia. Dr. Ghadimi has served on the Editorial Board for the Journal of Cardiothoracic and Vascular Anesthesia since 2018 and has served as a peer reviewer for more than 30 top-medical journals worldwide.
Over his career, he has developed a global multidisciplinary network of collaborators and colleagues in academic medicine, private practice, larger healthcare systems, and offices of the federal government. He has experience with grant funding from a variety of sponsors, including federal, industry, foundation, philanthropy, and institutional sources. He also holds positions on several other national and international committees aimed at improving cardiovascular health in patients undergoing surgery and post-surgical intensive care. He is a selected task force and writing committee member of the 2024 American College of Cardiology and American Heart Association Perioperative Cardiovascular Guidelines. He has devoted the majority of his career to the service of patients requiring cardiovascular perioperative and surgical intensive care.
In addition to a doctorate in Medicine, Dr. Ghadimi holds a Bachelor’s in Economics from Boston University and a Master’s in Clinical Research from Duke University School of Medicine and the National Institutes of Health. He is also an inventor with patents/patents pending, a medical consultant, a mentor, and an investor. He is a founding member and the original academic director of True Learn, an eLearning company focused on board exam preparation for multiple medical subspecialties. This resource is used by many physicians around the country. Beyond developing an educational platform that has reached several thousand physicians and physicians-in-training, Dr. Ghadimi has formally mentored 22 pre-doctorate and post-doctorate trainees, with several mentees continuing their faculty careers in academic practice. In addition, he serves as a resource for a multitude of other physicians, physicians-in-training, and allied healthcare professionals.
Currently, Dr. Ghadimi serves as Director of the Clinical Research Unit for the Department of Anesthesiology at Duke Health, leading a cohesive, high-performing management team that oversees 45 staff working with Anesthesiology faculty and faculty in other departments to operationalize more than 80 innovative research protocols annually (single- and multi-site studies) to advance the fields of perioperative medicine, intensive care, pain management, and brain and heart health. He is leading digital health and artificial intelligence implementation in research workflow to rapidly leverage capabilities for automation and efficiency with the evolving guidance of cybersecurity compliance. He has also led the expansion of the Human Biospecimen Repository within the Department of Anesthesiology, where participants from prospective studies have generously donated biofluids and tissue for the advancement of disease-specific biology and translational research. Dr. Ghadimi is currently involved in the One Duke Gen precision medicine initiative for Duke Health to catalyze high-impact translational discoveries through expansive data-driven partnerships.
Yi-Ju Li
My research interest is in statistical genetics, including statistical method development and its application for understanding the genetic predisposition of human complex diseases. Here is the list of research topics:
- Statistical genetics: development of family-based association methods for quantitative traits with or without censoring and for detecting X-linked genes for disease risk. With the availability of next generation sequencing data, we have ongoing projects to develop the association methods for testing rare variants for different phenotypic measures.
- Genetics of Alzheimer's disease (AD) and Fuchs endothelial corneal dystrophy (FECD).
- Genetic basis of age-at-onset of Alzheimer disease.
- Peri-operative genomic studies. Investigate the genetic risk factors for postoperative outcomes of patients underwent non-emergent coronary artery bypass grafting with cardiopulmonary bypass.
Jeffrey Giles Gaca
Thomas Lee Ortel
My research program investigates the molecular mechanisms whereby various congenital and acquired abnormalities result in ‘dysfunctional’ hemostasis (i.e., hemorrhage or thrombosis) to better understand the molecular mechanisms and interactions that are necessary for normal hemostasis. We are particularly interested in the mechanisms whereby antibodies and other inhibitors can interfere with normal hemostatic mechanisms. Several projects extensively overlap and focus on the assembly and function of procoagulant (e.g., factor X-ase and prothrombinase) and anticoagulant (e.g., activated protein C complex) phospholipid membrane-dependent complexes.
We utilize a variety of approaches in these studies. Monoclonal antibodies, single-chain variable domain fragments, polyclonal antibodies prepared from patients with factor VIII inhibitors, and site-specific mutagenesis have all been used to characterize structure-function relationships in coagulation factor VIII. Our laboratory has also extensively characterized anti-factor V antibodies, investigating autoantibodies as well as xenogenic antibodies developing after exposure to topical bovine thrombin preparations which contain trace amounts of contaminating bovine factor V. We have also characterized how antiphospholipid antibodies interfere with the activated protein C complex, a lipid-dependent natural anticoagulant complex that proteolytically inactivates factor Va and factor VIIIa.
Our current studies are focusing on two antibody-mediated thrombotic syndromes, heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. First, we are initiating a large clinical trial investigating the incidence of clinically-significant heparin-induced thrombocytopenia in patients who develop anti-heparin/platelet factor 4 antibodies following cardiac bypass procedures. While these antibodies are commonly seen following cardiac bypass, the true incidence of thromboembolic complications related to these prothrombotic antibodies remains unknown. We are also collaborating with investigators in the Center for Human Genetics on a large, multi-center study exploring the genetics of familial antiphospholipid antibody syndrome. In addition, we have used a genomic strategy to investigate patients with antiphospholipid antibody syndrome and have identified a gene expression profile that appears to be unique to patients with this syndrome in contrast to patients with venous thromboembolism who do not have these autoantibodies.
We also participate in a variety of collaborative research efforts, both with individual investigators as well as participating in multi-center clinical research studies. For example, we are one of seventeen centers participating in the NIH-supported Transfusion Medicine/Hemostasis Network, and we are currently conducting a trial through this network to define the optimal dose of platelets for patients needing platelet transfusions for hypoproliferative thrombocytopenia. We are also part of a multi-center registry of patients with thrombotic thrombocytopenic purpura, and we are one of eight centers in the Hemostasis and Thrombosis Center pilot program sponsored by the Centers for Disease Control and Prevention. Participation in these registries and networks provides us with access to the patient populations that we study in the research laboratory.
Jerrold Henry Levy
Jerrold Levy is Professor of Anesthesiology, Critical Care, and Surgery (Cardiothoracic) at Duke University Medical Center in Durham, NC. He obtained his medical degree from the University of Miami, where he was an intern in internal medicine, and undertook his residency in the Department of Anesthesiology of the Massachusetts General Hospital and Harvard Medical School in Boston, where he was also Chief Resident, and completed fellowships in both Respiratory ICU and Cardiac Anesthesiology. He previously was Professor, Deputy Chair for Research, and Chief of Cardiothoracic Anesthesiology at Emory University School of Medicine. His clinical and research interests include anticoagulation and its reversal, therapeutic strategies to prevent and treat coagulopathy and acute inflammatory responses in critically ill patients, clinical applications of recombinant and purified protein concentrates to treat bleeding, and pharmacologic approaches to treat shock. He is currently Chair of the Subcommittee on Perioperative and Critical Care Thrombosis and Hemostasis for the International Society of Thrombosis and Hemostasis, Executive Editor of Anesthesiology, and consultant to the FDA‘s Biologic Products Advisory Committee. He is the author of over 450 publications on PubMED, with over 100,000 citations on Google Scholar and a h-index of 95. He is also fluent in French and conversational in Spanish and Japanese.
Ian James Welsby
As a practicing cardiothoracic anesthesiologist, I have contributed to the better understanding of the management and of perioperative thrombosis (particularly HIT). This has been as a Duke site PI for the Rare Thrombotic Diseases Consortium led by Dr T.L Ortel and a clinical collaborator with the basic and translational science approach to HIT led by Dr G Arepally. I have also championed novel approaches to dealing with perioperative HIT such as plasmaperesis.
Similarly, I have been a local leader in establishing management of transfusion approaches to major cardiac surgery including the novel introduction of autologous plateletpheresis to limit exposure to allogeneic platelet transfusions in this highly transfused population, identifying the transfusion requirements during thoracic aortic reconstruction and promoting use of a lower dose of rFVIIa use in this population, changing established clinical practice.
My research interests focus on perioperative transfusion and hematology concerns. Recently, Dr Kor (Mayo Clinic) and I received a multiple PI R-01 award to evaluate point-of-care/bedside washing of packed red blood cells to reduce perioperative lung injury. This novel repurposing of commonly available “cell-saver” technology is, for most surgical cases, the only practical means of delivering a washed product, and promises to be a critical advancement in perioperative transfusion medicine. I also have a longstanding interest in the rejuvenation of RBCs to normalize oxygen delivery capacity of transfused RBCs. Such a development will be of tremendous importance to transfusion practice, particularly for highly transfused populations and with current threats to blood banking inventory.
In summary, I have dedicated my research career to improving the outcome of patients undergoing cardiothoracic surgery, understanding perioperative coagulopathy, and optimizing transfusion practice.
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