Hemorrhage due to uncontrolled bleeding is a clinical problem commonly faced by clinicians managing traumatic injury, surgical patients, and obstetrical patients. There are many terms used to describe this life-threatening problem, including massive transfusion coagulopathy or trauma-induced coagulopathy. The complex coagulopathy that occurs in these situations further compromises the efficacy of subsequent hemostatic treatments. Tissue injury due to trauma, surgical interventions, following delivery in obstetrical patients, or associated with extracorporeal circulation during cardiopulmonary bypass or extracorporeal membrane oxygenation may also contribute to the coagulopathic state.
Hemostasis is a physiologic response to vascular injury and disruption of the vascular endothelium and has been described in earlier chapters. Following surgery or trauma where there is extensive tissue injury, in addition to massive loss of blood, the endothelial integrity is compromised; the coagulopathy that follows tissue injury and blood loss produces a complex alteration in the vasculature often described as an endothelialopathy. Loss of the critical aspects of vascular regulation can also manifest as disseminated intravascular coagulation (DIC), a perturbation of the balance between anticoagulant and procoagulant effects.
The management of hemostasis following traumatic injury and life-threatening hemorrhage has significantly changed over the years from initial resuscitation with crystalloid/colloids and red blood cells (RBCs) to routine administration of plasma/fresh frozen plasma (FFP) and platelets in addition to red cells. Experiences learned from the battlefield and civilian studies have been critical for developing multiple therapeutic approaches that have been combined in a rational massive transfusion protocol. Retrospective studies have reported improved survival with the initial use of plasma and platelets as part of these protocols. This chapter will review the physiology of massive transfusion and modern therapeutic approaches.
Pathophysiology of Hemostatic Abnormalities Associated with Trauma
Hemorrhage is a major cause of mortality following traumatic injury and responsible for approximately 50% of deaths within 24 hours of injury and approximately 80% of intraoperative trauma deaths.1 The evolution of fluid resuscitation initially included crystalloid, followed by RBC transfusions, and the addition of FFP/plasma, platelets, and cryoprecipitate either empirically or as guided by additional laboratory testing. Therapy in the past was based on treating coagulopathy after the initial resuscitation and stabilization of the patient. More recent observations in trauma victims and on the battlefield found that early administration of plasma resulted in earlier improvement, whereas several studies reported that use of large crystalloid volumes were associated with increased bleeding and lower survival.1–3
Trauma and Endothelial Dysfunction
The effects of hemorrhagic shock on endothelial function have been described and the term endotheliopathy of trauma has been proposed to describe the systemic endothelial injury and dysfunction that contributes to coagulopathy, inflammation, vascular permeability, tissue edema, and multiorgan system dysfunction.1,2 The endothelial dysfunction is secondary to vascular injury and other factors that result from shock, ischemic injury, and the release of inflammatory mediators. Plasma repletion is thought to have a restorative function on endothelial tight junctions to better modulate vascular integrity compared to crystalloid studying in vitro models. Plasma contains multiple serine protease inhibitors that may have antiinflammatory effects. The endothelium becomes permeable with hemorrhagic shock and extravascular fluid is mobilized intravascularly. Plasma contains proteins for osmotic maintenance but there are also multiple serine protease inhibitors that include antithrombin (also called antithrombin III), C1 esterase inhibitor, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), α2-antiplasmin, and other inhibitors that may be critical for antiinflammatory responses. Crystalloids lack these factors and are thought to increase interstitial edema, increase lung injury, and promote multiorgan system dysfunction.1,2
Inflammatory activation following tissue injury contributes to the endothelial dysfunction as does the critical role of fibrinolysis. With tissue injury, the fibrinolytic system is activated converting plasminogen to plasmin, a critical enzyme that cleaves fibrin. Plasmin and its generation are inhibited by PAI-1, by thrombin-activatable fibrinolysis inhibitor (TAFI), and by α2-antiplasmin. Thus, fibrinolysis is regulated by multiple circulating serine protease inhibitors under physiologic conditions that can be depleted with massive hemorrhage. As a result of this pathologic activation, antifibrinolytic therapy is a critical component of a multimodal approach, the success of which has been reported in multiple patient populations undergoing surgery. In addition to contributing to a bleeding diathesis, plasmin generation causes a multitude of other effects, including cell signalling, proinflammatory responses, and activation of the complement cascade.4
Massive Transfusion
Massive transfusion is defined as greater than 10 units of RBCs within 24 hours after initiating treatment and occurs in approximately 10% of military trauma and approximately 5% of civilian trauma patients.1,2 Patients who acutely bleed and receive greater than 10 units of RBCs within 6 hours of a trauma have a higher mortality. However, the massive transfusion itself is likely a marker for more severe injury rather than a direct effect of the transfusions. The development of massive transfusion strategies and use of specific protocols improves survival and has been an important evolution in the management of trauma patients, wartime injuries, and even massive hospital bleeds that occur following postpartum hemorrhage or massive surgical bleeding.
Therapeutic Approaches for Massive Transfusion and Coagulopathy
Transfusion services, blood bankers, clinicians, and hospitals have developed and implemented protocols to rapidly provide blood products for patients suffering acute and massive hemorrhage. Observational studies and retrospective analyses of military and civilian trauma initially reported improved outcomes with the administration of whole blood or whole blood equivalents with massive transfusion that include transfusion ratios of 1:1:1 for RBCs, plasma, and platelets.1,2 However, there is also conflicting data suggesting increased morbidity and mortality associated with plasma product transfusion. Recent studies evaluating the critical plasma ratios in trauma and will be considered in more detail later in this chapter.5
Adverse Effects of Transfusions
All transfusions have risk and certain concerns regarding plasma are important. Major life-threatening risks of plasma administration include transfusion-related acute lung injury, transfusion-associated circulatory overload, hemolytic transfusion reactions, and anaphylaxis (these phenomenons have been discussed in an earlier chapter, Chapter 28, Blood Products and Blood Components. Deciphering the causes of adverse outcomes following transfusions can be difficult because more critically injured patients who have worse outcomes will also require more transfusions, and the reason underlying the need for transfusion will invariably cloud any interpretation of the clinical outcomes.
Hemostatic Changes Associated with Massive Transfusion Coagulopathy
Hemostatic abnormalities following massive transfusions and/or trauma can develop as a result of multiple factors not necessarily directly related to blood administration. Along with coagulopathy, hypothermia and acidosis complete the triad that results in higher mortality in the management of acute trauma. These factors may play a role in the localized depletion or decreased function of hemostatic factors through blood loss, tissue injury, and/or consumption of factors. Volume resuscitation with crystalloids, colloids, and RBCs or the use of cell salvage systems following blood loss can lead to dilutional coagulopathy. The hemostatic balance between anticoagulant and procoagulant activity may be lost due to tissue injury following trauma (including head trauma), tissue hypoxia/acidosis, burns/sepsis, or other physical events especially in an intraoperative setting from suction and reinfusion of debris.
Hypothermia can be a critical factor that precipitates or worsens coagulopathy, as enzymatic cascades are impaired; this impairment may appear beginning at even small drops in core body temperatures, even as high as 35°C. Platelet function may also be impaired with hypothermia, and platelet dysfunction can also occur due to increased fibrinogen degradation products (FDP) and D-dimer levels. Other important considerations include anemia-related factors, that is, decreased RBC adenosine diphosphate and decreased platelet diffusivity; and the effects of acidemia, which may include hypocalcemia with massive transfusions.
Perioperative Hemostatic Changes
Trauma and surgical patients have varied degrees of vascular injury and exsanguination. Blood loss up to 30% of total blood volume is generally well tolerated with the fluid resuscitation alone. Coagulation factors are progressively diluted to 30% of normal after a loss of one blood volume, and down to 15% after a loss of two blood volumes.6 With severe hemodilution, thrombin generation, a critical step in clot formation is impaired by reduction in procoagulant levels. Thrombin generation is also impaired by thrombocytopenia. Additionally, fibrinogen and factor XIII, critical substrates for clot formation also decrease without appropriate factor replacement during volume resuscitation. Although clot may form, low levels of fibrinogen and/or factor XIII will result in reduced clot strength, a finding that is often monitored with viscoelastic blood monitoring using thromboelastography or thromboelastometry. Low levels of clotting proteins affect the ability of fibrin to polymerize.6
Massive Transfusion Coagulopathy
Because standard laboratory tests often take too long to obtain, and with severe hemorrhage, several blood volumes may be replaced by the time the results are available, laboratory testing plays an uncertain role in decision making in many settings where massive transfusion is necessary. Thus, transfusion protocols have been developed where fixed doses of FFP and platelets are administered after a specific number of RBC units have been given, often in a 1:1:1 ratio.6 Whether these fixed ratios prevent the development of coagulopathy or improve bleeding is not well established in cardiac surgery, but in trauma patients and in noncardiac surgical battlefield conditions, there is growing data that fixed ratios improve survival.7,8
With life-threatening hemorrhage, as seen in trauma patients, transfusion of fixed ratios of RBCs, FFP, and platelets should be administered.6 Transfusion with fixed plasma/FFP:platelet:RBC ratios report a survival benefit. As a result, the Army Surgeon General established a clinical policy of 1:1:1 (plasma/FFP:platelets:RBCs) for combat casualties expected to receive massive transfusion. One large study of civilian massive transfusion patients demonstrated improved survival with increased use of platelets.8 The current U.S. military resuscitation practice is to use a balanced approach, using 1:1:1 as the primary resuscitation fluid for the most seriously injured casualties (http://www.cs.amedd.army.mil/borden/book/ccc/UCLAchp4.pdf). Current studies are underway to determine what the optimal ratios should be in a variety of clinical settings.
Role of Red Blood Cells and Anemia
Anemia may also contribute to bleeding as reported in nonsurgical patients due to multiple mechanisms that include nitric oxide scavenging, margination of platelets, and contributions to the hemostatic processes, although the ideal hematocrit to minimize this risk is not clear. RBC transfusions are administered for multiple reasons and they are increasingly recognized for their critical role in hemostasis. RBCs can release adenosine diphosphate, an important activator of platelets. Platelets also contribute a surface for clot initiation by facilitating thrombin generation.6 Studies suggest that the FXIII activation and fibrin cross-linking may play an important an important role in mediating RBC retention within clots.
Causes of Bleeding in the Setting of Massive Transfusion Coagulopathy
Risk factors for developing massive transfusion coagulopathy are often related to the surgical or traumatic injury that causes the hemorrhage. Patients should be evaluated for use of additional medications that can affect coagulation, including antiplatelet agents (clopidogrel, prasugrel, ticagrelor), anticoagulation agents (dabigatran, rivaroxaban, apixaban, warfarin), or parenteral agents such as low-molecular-weight heparin.9 Monitoring these agents has been reviewed in other chapters. Many of the standard coagulation tests used for evaluating hemorrhage cannot adequately determine the effects of antiplatelet agents (e.g., aspirin, clopidogrel, prasugrel, or ticagrelor) as the complex platelet function tests used clinically are usually ineffective with significant bleeding.
Hypothermia, Acidosis, and Coagulopathy
Hypothermia has multiple effects because coagulation is an enzymatic process. As patient temperature decreases, the enzymatic processes that function maximally at normal body temperature are impaired. Hypothermia can produce multiple hemostatic defects that include reversible platelet dysfunction and increased fibrinolysis.10 In addition, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged at temperatures of 34°C or less when compared with measurements at 37°C.10 When blood is sampled from a hypothermic patient, the test is actually conducted at 37°C, so the influence of hypothermia on coagulopathy and bleeding may not be readily appreciated by clinicians. Overall, hypothermia is an important contributing factor to the bleeding defect in coagulopathy in trauma patients and is part of the lethal triad defined as hypothermia, acidosis, and coagulopathy. Hypothermia and acidosis can also prevent thrombin generation, a critical component of clot formation. Hypothermia is thought to inhibit the initiation phase, whereas acidosis severely inhibits the propagation phase of thrombin generation.11Maintenance of normothermia is important as part of a multimodal therapeutic plan for minimizing blood loss with significant hemorrhage in trauma, surgery, or coagulopathy of any cause. In a perioperative setting, blood warmers and other warming devices should be used to prevent and treat hypothermia.
Dilutional Coagulopathy
Before the development of massive transfusion protocols, dilutional coagulopathy was a common cause of bleeding in the actively hemorrhaging patient. Bleeding and coagulopathy associated with massive transfusions in 21 acutely traumatized soldiers that occurred after transfusion of 20 to 25 units of stored whole blood was described.12 In this report, dilutional thrombocytopenia was a primary cause of the bleeding and was thought to be due to decreased platelet levels in stored blood. Transfusion of approximately 15 to 20 units caused significant dilution of blood volumes, and critical decreases in platelet count to approximately 20,000 to 30,000/mm3, far below the recommended platelet target goals in actively bleeding patients.12
Fibrinolysis
Fibrinolysis is a critical component of preventing excessive clot formation and balances for hemostasis but excessive fibrinolysis as occurs commonly in trauma patients can cause bleeding. Fibrinolysis is initiated by mechanisms that include stimulating tissue plasminogen activator (tPA) release in response to vascular endothelial damage, stress responses, and other mechanisms.4 Plasmin degrades fibrinogen and von Willebrand’s factor (vWF), cleaves receptors from platelets (glycoprotein Ib), and creates degradation products that bind glycoprotein IIb/IIIa receptors, thus interfering with platelet function. Contact activation associated with tissue injury and hemostatic activation also activates kallikrein that initiates plasmin generation but also is involved in other proinflammatory steps including neutrophil chemotaxis and chemokinesis.4 Contact activation leads to the cleaving of glycoprotein Ib receptors from platelets, and generation of FDP resulted in the creation of multimers that bind with glycoprotein IIb/IIIa receptors to prevent platelet–fibrinogen cross-linking, similar to the effects of the glycoprotein IIb/IIIa receptor inhibitor, abciximab.13 These alterations in fibrinolysis adversely affect platelet function.
Hypofibrinogenemia
Fibrinogen is a critical component in clot formation and an acute-phase reactant protein. Fibrinogen circulates in the highest concentration of all of the coagulation factors, and normal values for plasma levels are approximately 200 to 400 mg/dL but increase in pregnancy and as a nonspecific anabolic postoperative response following tissue injury.14 In the late stages of pregnancy, the normal physiologic response is hypercoagulability to reduce the risk of bleeding complications during birth. Although benign dilutional thrombocytopenia often develops, with a platelet count of 80,000 to 150,000/mm3, fibrinogen levels increase to approximately 400 to 600 mg/dL. During delivery, a systemic hemostatic state develops with consumption of platelets and coagulation factors (including fibrinogen) to allow clotting to occur; hemostasis then normalizes within 4 to 6 weeks postpartum.14
If fibrinogen levels fall to approximately 80 to 100 mg/dL, standard clot-based coagulation tests including PT and partial thromboplastin time (PTT) can be affected. These changes may not be corrected by transfusion of FFP/plasma; however, cryoprecipitate is used or fibrinogen concentrates in countries that do not have cryoprecipitate (see earlier chapters on blood and hemostasis). Older transfusion algorithms only recommend initiating treatment when fibrinogen levels are less than 100 mg/dL and it may be difficult to reverse the effects of such low levels of this vital component of hemostatic function. European guidelines have focused on the role of normal fibrinogen levels in the bleeding patient, and recent studies also support the potential blood-sparing effects of fibrinogen concentrates.14
Monitoring Hemostasis during Massive Transfusion
PT and aPTT are often used for monitoring coagulopathy during massive transfusion. The PT is considered proportional to coagulation factor loss and/or hemodilution but other factors may also be responsible. These standard coagulation tests have limitations for evaluating bleeding because of the multiple coagulation defects that occur. Standard plasma-based coagulation tests also do not provide information about platelet function or interactions with coagulation factors and can be prolonged even with normal clotting factor levels due to protein C deficiency. As a result, other coagulation tests are being used more and more for managing massive transfusions.
Whole blood viscoelastic measurements continue to expand for management of trauma, perioperative bleeding, and massive transfusion coagulopathy and include either thromboelastography (TEG; Hemonetics Corporation, Braintree, MA) or thromboelastometry (ROTEM; TEM International, Cary, NC). Some of the advantages of using these systems include the ability to rapidly have information for the diagnosis and management of coagulopathy and also provide methods for algorithm- and goal-directed management. Thromboelastometry provides information about clot formation and fibrin polymerization and its use has been reported for evaluating abnormal trauma-induced coagulopathy.6 The clot strength as determined by maximal amplitude on TEG and maximal clot firmness on ROTEM is influenced by fibrinogen levels but also by platelet contributions to the clot. In addition, using the ROTEM FIBTEM assay, systemic fibrinogen levels can be rapidly determined. The role of these advanced tests during massive transfusion continues to evolve as therapeutic strategies for transfusion and treatment algorithms are developed. In European countries where cryoprecipitate may not be available, these assays are used as therapeutic guides for both fibrinogen concentrate and prothrombin complex concentrate administration.6
Treatment of Coagulopathy during Massive Transfusion
A flow chart and example for the activation and institution of a massive transfusion protocol are shown in Figures 31-1 and 31-2. Specific considerations for the management have been discussed and are also included in the following perspectives regarding individual component therapy.
Plasma/Fresh Frozen Plasma
Overall, developing massive transfusion protocols has been an important therapeutic tool for effectively managing life-threatening hemorrhage after trauma.15 Plasma/FFP contains multiple factors for hemostasis and has increasingly been considered a critical component. Most of the analyses reporting beneficial effects of high plasma ratios are retrospective and include plasma/FFP transfusion:RBC ratios of 1:1 or more from trauma. The optimal ratio of plasma/FFP:RBCs is not known, but prospective studies including a current investigation from the North American Pragmatic, Randomized Optimal Platelets and Plasma Ratios study (ClinicalTrials.gov number, NCT01545232) will provide new information. This randomized trial from 12 different medical centers will evaluate outcomes from trauma patients who will require massive transfusions as defined by the administration of more than 10 units of RBCs within 24 hours and will assess overall mortality. There are major differences in the management of severe hemorrhage between the United States and Europe. Based on currently published European guidelines, clinicians are now using factor concentrates based on thromboelastometry (ROTEM) guidance, with prothrombin complex concentrates, fibrinogen, and factor XIII. Fibrinogen and other factor concentrates have been used for many years in Europe, as cryoprecipitate is not available in all countries. However, therapy is multimodal and requires hemodynamic and hemostatic support as well as efforts to address the underlying bleeding source. An example of a massive transfusion protocol is shown in Figure 31-1.6
Platelet Administration
Following traumatic injury or significant postoperative bleeding, the critical platelet count for transfusion is often based on consensus therapy rather than true objective data. Although a count of 50,000 or more is recommended, the threshold for administration of platelets, especially in cases of dilutional coagulopathy, remains unclear as do the ideal ratio of platelets to other blood components. Most protocols attempt to develop a strategy that mimics whole blood replacement with RBC:plasma/FFP: platelets at a 1:1:1 ratio with massive bleeding.13,14
However, assessing platelet function in the bleeding patient is not possible; therefore, empiric platelet administration is often undertaken. If patients have received antiplatelet agents recently, then even the existing platelets and platelet counts may not be helpful. Therefore, if patients have received antiplatelet agents or are bleeding after separation from cardiopulmonary bypass, then platelet dysfunction should be suspected and platelet concentrates considered. However, there are significant potential adverse events associated with platelet administration.6
Antifibrinolytic Agents
Because of the critical role of fibrinolysis with severe bleeding and trauma, the antifibrinolytic agent tranexamic acid is increasingly used as a therapeutic strategy. Inhibiting fibrinolysis during acute bleeding has many beneficial effects including preserving initial clot formation at a bleeding site that may otherwise be broken down, similar to the clot destruction seen in hemophilia.6 The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH 2) study focused on tranexamic acid as a therapeutic agent in traumatic injury in a prospective randomized placebo-controlled trial of 1-g loading followed by 1 g over 8 hours in 20,211 trauma patients. Overall mortality was reduced from 14.5% to 16.0% (relative risk, 0.91; P = 0.0035), as were deaths due to bleeding (4.9% vs. 5.7%; relative risk, 0.85; P = 0.0077). Tranexamic acid is also approved in the United States for excessive menstrual bleeding at a dose of 1.3 g three times a day (~4 g total dose), without significant reported safety issues. Despite the efficacy and safety of tranexamic acid, clinicians often substitute epsilon-aminocaproic acid, another lysine analog, although this agent has not been studied as well as tranexamic acid and is not available in some European countries.
Procoagulants
Multiple other agents have been used or studied in trauma and massive transfusion coagulopathy, including recombinant activated factor VII and prothrombin complex concentrates. The off-label use of many of these agents to increase clot formation following major surgery and or traumatic injury is a reasonable but empiric approach for treating life-threatening bleeding and often used as a “last-ditch effort” in patients with ongoing bleeding and at risk for death or other adverse events. When clinicians are presented with a patient who continues to bleed despite standard therapeutic interventions, they have two choices. They can either continue to give their standard interventions (that have already failed to work) or administer a procoagulant such as recombinant activated factor VII and prothrombin complex concentrates. Clinicians are justified in choosing a procoagulant plan of action for several reasons.16 First, it is clinically evident that patients with massive refractory bleeding will have adverse outcomes unless the blood loss is controlled in a timely manner. Second, persisting with standard interventions will likely not achieve this goal and will unnecessarily expose patients to the risks of excessive blood product administration. Third, the efficacy and safety data from most randomized trials are not applicable to these situations because patients with refractory bleeding were not studied. Fourth, even if the safety data from randomized trials do apply, which all suggest that procoagulants by virtue of their effects increase the risk of thromboembolic complications, this risk is relative to that of allowing bleeding and exsanguination to occur. Fifth, observational data from Europe and some randomized trial data in bleeding patients suggests that use of procoagulant therapy and concentrates is effective for refractory blood loss using factor concentrate driven algorithms. Finally, given the ethical implications and impracticality of such trials, it is unlikely that additional applicable data from placebo-controlled randomized trials to evaluate life-threatening hemorrhage will ever be performed.
Postpartum Hemorrhage
Postpartum hemorrhage is an important cause of life-threatening hemorrhage and continues to be a major cause of maternal mortality.17 A recent published report from an international expert panel in obstetrics, gynecology, anesthesiology, hematology, and transfusion medicine performed a comprehensive literature review to identify patients at high risk of adverse outcomes.17 They defined severe persistent postpartum hemorrhage as “active bleeding greater than 1,000 mL within the 24 hours following birth that continues despite the use of initial measures including first-line uterotonic agents and uterine massage.” As in all life-threatening bleeding, a treatment algorithm that includes a massive transfusion protocol is important. The group suggested coagulation testing should be performed to guide therapy. If initial therapy fails to stop bleeding and uterine atony persists, second- and third-line interventions, including mechanical or surgical maneuvers, that is, intrauterine balloon tamponade or hemostatic brace sutures with hysterectomy are the final surgical option for uncontrollable bleeding.17 Pharmacologic options include hemostatic agents, including tranexamic acid along with a massive transfusion protocol for blood product administration are also critical to minimize blood loss and optimize clinical outcomes in management of women with severe, persistent postpartum hemorrhage.17
Multimodal Resuscitation: Damage Control Resuscitation
Managing life-threatening and uncontrolled bleeding is a clinical problem that can occur following traumatic injury, during major surgical procedures, and following delivery. From information learned from combat and battlefield casualties, a multimodal and multispecialty approach has evolved that includes perspectives from surgeons, anesthesiologists, emergency medicine physicians, and transfusion medicine specialists for the optimal resuscitative approach to hemorrhagic shock.1,10,18 Clinicians and investigators from multiple specialties have coined the term damage control resuscitation, a multimodal strategy.19This concept calls for (a) early and increased use of plasma, platelets, and RBCs while minimizing crystalloid use; (b) hypotensive resuscitation strategies; (c) avoiding hypothermia and acidosis that may compound coagulopathy; (d) use of adjuncts such as calcium, THAM (tris-hydroxymethyl aminomethane, an alternate alkalizing agent to sodium bicarbonate), and tranexamic acid and off-label uses of procoagulation agents; and (d) early definitive hemorrhage control.19
Summary
Coagulopathy associated with massive transfusion is a complex, multifactorial clinical problem. When evaluating the causes of coagulopathy in this setting, preexisting pharmacotherapy including prior use of anticoagulants must be considered. The role of hypothermia, dilutional coagulopathy, platelet dysfunction and fibrinolysis should also be considered. Evaluating fibrinogen levels represents a critical aspect of all transfusion algorithms, especially for patients with massive transfusion and life-threatening hemorrhage. Transfusion algorithms are a critical and relatively new aspect of perioperative management; they attempt to provide adequate factor and hemostatic replacement, although the ideal ratio of various blood components and factor concentrates are still being determined. Significant changes in management have become important in resuscitation strategies and crystalloids are no longer a primary means of resuscitation; the primary strategy now is replacing acute blood loss with plasma and platelet-containing products instead of early and large amounts of crystalloids and RBCs.1 Templates for a massive transfusion protocol and activation of a massive transfusion protocol are included in Figures 31-1 and 31-2. Several excellent reviews are available for additional reading on this subject.1,2,6,18
References
1. Holcomb JB, Pati S. Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon’s perspective. Hematology Am Soc Hematol Educ Program. 2013;2013:656–659.
2. Holcomb JB. Optimal use of blood products in severely injured trauma patients. Hematology Am Soc Hematol Educ Program. 2010;2010:465–469.
3. Cotton BA, Au BK, Nunez TC, et al. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. J Trauma. 2009;66:41–48; discussion 8–9.
4. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet. 2010;376:3–4.
5. Goodnough LT, Spain DA, Maggio P. Logistics of transfusion support for patients with massive hemorrhage. Curr Opin Anesthesiol. 2013;26(2):208–214.
6. Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology. 2010;113:1205–1219.
7. Dente CJ, Shaz BH, Nicholas JM, et al. Improvements in early mortality and coagulopathy are sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a civilian level I trauma center. J Trauma. 2009;66:1616–1624.
8. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447–458.
9. Levy JH, Faraoni D, Spring JL, et al. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology. 2013;118:1466–1474.
10. Levy JH. Massive transfusion coagulopathy. Semin Hematol. 2006;43:S59–S63.
11. Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma. 2009;67:202–208; discussion 8–9.
12. Miller RD, Robbins TO, Tong MJ, et al. Coagulation defects associated with massive blood transfusions. Ann Surg. 1971;174:794–801.
13. Rinder CS, Mathew JP, Rinder HM, et al. Modulation of platelet surface adhesion receptors during cardiopulmonary bypass. Anesthesiology. 1991;75:563–570.
14. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion. 2014;54:1389–1405.
15. Roback JD, Caldwell S, Carson J, et al. Evidence-based practice guidelines for plasma transfusion. Transfusion. 2010;50:1227–1239.
16. Karkouti K, Levy JH. Recombinant activated factor vii: the controversial conundrum regarding its off-label use. Anesth Analg. 2011;113:711–712.
17. Abdul-Kadir R, McLintock C, Ducloy AS, et al. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel [published online ahead of print March 12, 2014]. Transfusion.
18. Levy JH, Dutton RP, Hemphill JC III, et al. Multidisciplinary approach to the challenge of hemostasis. Anesth Analg. 2010;110:354–364.
19. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62:307–310.