Understanding Excessive Bleeding in Trauma Patients
By: Sandro Rizoli, MD, PhD, FRCSC, FACS
While cancer and cardiovascular disease strike mostly elder people, trauma strikes the young when they are at the peak of their productive lives—trauma is the leading cause of death in Canadians below age of 40. The first cause of death among these patients is severe head injury and the second is bleeding, which is also the first cause of preventable death.
Traumatized patients rapidly become coagulopathic: they cannot clot appropriately, which leads to profuse bleeding and sometimes death. It was initially thought that traumatized patients became coagulopathic because of dilution and loss/consumption of clotting elements. However, in 2003, Brohi and colleagues1 proposed a primary (or inherent) defect in coagulation (or hemostasis) as being responsible for the early trauma coagulopathy, which can be worsened by dilution. Though this paper brought our understanding of trauma-related coagulopathy much further, the mechanisms leading to early (first few hours) trauma coagulopathy are poorly understood and are the focus of my research.
Research I – A look into the mechanisms of coagulopathy
A few studies by our group at Sunnybrook Health Sciences Centre (SHSC), which includes Dr. Callum (Transfusion Medicine), Dr. Nascimento (Surgery), Dr. Reis (Clinical Pathology), Dr. Trpcic and Dr. Coroux (Research), have shown that following the trauma, the body releases both a potent anticoagulant called Activated Protein C (APC) and a fibrinolytic agent called tissue Plasminogen Activator (tPA).2,3,4 TPA is used clinically in patients with myocardial infarction and stroke to lyse the clot and allow flow of blood to ischemic heart/brain. It is the combination of APC and tPA that result in an anticoagulated trauma patient—a patient who is incapable of forming strong enough clots to stop bleeding. The anticoagulation can occur in varying degrees and promptly “dissolves” (lyse) clots that are formed. This phenomenon is called hyper fibrinolysis.5,6 In addition, our team discovered that the “antidotes” to APC and tPA, such as PAI-1 and TAFI, are depressed, worsening the anticoagulation and excessive fibrinolysis.
The combination of multiple hemostatic defects that vary over time and in response to different medical interventions result in a very complex picture. It also explains why it is so difficult to study trauma coagulopathy, particularly soon after the trauma. Furthermore, precisely identifying the hemostatic defects may change how each patient is treated. There is no prescribed formula on how to best treat these patients since there is so much variation and the ideal treatment must be tailored to the present needs of each individual patient.
Another problem in treating coagulopathic patients is that the laboratorial diagnostic tests have many limitations.7 Firstly, many assays can take days for the results to be ready, making them useless for directing the resuscitation of patients immediately after trauma. Secondly, there are only a few tests that can be done immediately after a trauma; these tests still take time to be done—often around one hour—which is enough time for the patient to die. Thirdly, they only evaluate particular portions of the hemostasis and there is no lab test to measure hyper fibrinolysis soon after the trauma.
To overcome these problems, we have been studying two similar equipments including thromboelastography (TEG) and thromboelastography (ROTEM) in trauma.8 These tests can be done at bedside, provide results in a matter of minutes, and give a picture of the whole hemostasis—from the initiation of clotting, to clot propagation, amplification, and lysis. At SHSC these machines are kept in the laboratory that is linked to the trauma room, operating room, and blood bank via large screens. The results are displayed in real time on these large screens as the test is being done. In using this equipment, clinicians can use the resulting graph to immediately identify which coagulation problems are occurring in a particular trauma patient and treat them—a truly “custom made treatment.” TEG and ROTEM are the only tests that diagnose hyper fibrinolysis in “real life trauma resuscitation.”5 Our team is conducting research to find TEG/ROTEM levels that, once reached, will automatically set off the blood bank to prepare blood products even before the physician requests them. The goal of this project is to reduce the time between diagnosing life-threatening coagulopathy and its treatment. It also allows the physician to focus on resuscitating the coagulopathic patient instead of wasting time interpreting lab tests and later ordering blood products.
Research II – Focus on clinical trials
In 2007, a series of retrospective studies9,10 proposed that all traumatized patients who are massively bleeding should be resuscitated with “whole” blood instead of saline solutions. Whole blood is obtained by transfusing patients with 1 unit of red blood cells for every 1 unit of plasma for every 1 unit of platelets (or 1:1:1 resuscitation). While this proposal rests on a sound rationale, so far no studies have conclusively proven this to be beneficial. These retrospective studies have methodological limitations (biases) limiting their power. There is also concern with the fact that blood is scarce, expensive, and has significant side effects (e.g. respiratory distress syndrome).
Our research team just finished the first randomized controlled trial (RCT) in the world, comparing 1:1:1 with standard resuscitation. Trying to enroll a massively bleeding patient (thus near death) while being actively resuscitated is very difficult and required major logistic planning and collaboration from many different groups within SHSC. In this study we did not find a survival advantage to 1:1:1. The manuscript is under consideration by a major journal.
Very recently, we started enrolling patients into a new multicentre RCT along with 11 other hospitals in the United States to test—once for all—whether 1:1:1 is the best way to resuscitate massively bleeding trauma patients. This study is funded by the National Institutes of Health, Canadian Institutes of Health Research, and Defense Research and Development Canada. It will take four years to complete and over 500 patients will be enrolled. We hope it will conclusively demonstrate the best way to resuscitate these patients.
The studies done by our group does at SHSC are all clinical in nature. The focuses are on understanding the mechanisms leading to early trauma coagulopathy and the best ways to diagnose and treat bleeding and coagulopathic patients. Our hope is to reduce the enormous burden of trauma worldwide.
MD, PhD, FRCSC, FACS
Professor of Surgery and Critical Care Medicine
University of Toronto
De Sousa Trauma Research Chair
President, Trauma Association of Canada
- Brohi K, Singh J, Heron M, Coats T: Acute traumatic coagulopathy. J Trauma. 2003 Jun;54(6):1127-30.
- Jansen JO, Scarpelini S, Pinto R, Tien HC, Callum J, Rizoli SB: Hypoperfusion in severely injured trauma patients is associated with reduced coagulation factor activity. J Trauma. 2011 Nov;71(5 Suppl 1):S435-40.
- Rizoli SB, Scarpelini S, Callum J, Nascimento B, Mann KG, Pinto R, Jansen J, Tien HC: Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma. 2011 Nov;71(5 Suppl 1):S427-34.
- Tien HC, Scarpellini S, Callum J, Tremblay L, Rizoli S: Assessing response to changing plasma/red cell ratios in a bleeding trauma patient. Am J Emerg Med. 2010 Jan;28(1):120.e1-5.
- Cotton BA, Harvin JA, Kostousouv V, Minei KM, Radwan ZA, Schöchl H, Wade CE, Holcomb JB, Matijevic N: Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012 Aug;73(2):365-70.
- Rizoli S, Nascimento B Jr, Key N, Tien HC, Muraca S, Pinto R, Khalifa M, Plotkin A, Callum J: Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence. J Trauma. 2011 Nov;71(5 Suppl 1):S441-7.
- Dzik WH, Blajchman MA, Fergusson D, Hameed M, Henry B, Kirkpatrick AW, Korogyi T, Logsetty S, Skeate RC, Stanworth S, MacAdams C, Muirhead B: Clinical review: Canadian National Advisory Committee on Blood and Blood Products–Massive transfusion consensus conference 2011: report of the panel. Crit Care. 2011;15(6):242. Epub 2011 Dec 8.
- Scarpelini S, Rhind SG, Nascimento B, Tien H, Shek PN, Peng HT, Huang H, Pinto R, Speers V, Reis M, Rizoli SB: Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res. 2009 Dec;42(12):1210-7. Epub 2009 Oct 30.
- Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007 Oct;63(4):805-13.
- Holcomb JB, Jenkins D, Rhee P, et al: Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007 Feb;62(2):307-10.