Current Opinion in Hematology:
Transfusion medicine and immunohematology: Edited by Martin L. Olsson
Hemostatic strategies for minimizing mortality in surgery with major blood loss
Johansson, Pär I
Regional Blood Bank, Section for Transfusion Service, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Correspondence to Pär I. Johansson, MD, MPA, Medical Director, Regional Blood Bank, Section for Transfusion Service, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Tel: +45 23729202; fax: +45 35390038; e-mail: firstname.lastname@example.org
Purpose of review: Continued hemorrhage remains a major contributor of mortality in massively transfused patients and controversy regarding their optimal management exists. This article reviews recent advances that impact the use and effectiveness of massive transfusion.
Recent findings: In the past 18 months, nine retrospective studies and three before and after studies have evaluated the implementation of massive transfusion protocols in massively transfused patients receiving more than 10 units of red blood cells (RBCs) within 24 h from arrival. All studies demonstrate that patients receiving a high fresh frozen plasma (FFP):RBC or platelet:RBC ratio have improved survival, with patients receiving both high FFP:RBC and platelet:RBC ratios exhibiting the highest survival rate. When whole blood thrombelastography is used to guide transfusion therapy in massively bleeding patients, an increase in FFP and platelet to RBC ratio is also seen, and this is associated with improved survival. This indicates that thrombelastography is better than conventional coagulation assays to monitor coagulopathy and predict transfusion requirements in massive bleeders.
Summary: Implementation of more aggressive hemostatic resuscitation strategies in massively bleeding patients seems reasonable, and optimally, thrombelastography should be used to monitor coagulopathy and guide FFP and platelet transfusions.
Persistent hemorrhage remains a major contributor to mortality in massively transfused patients, of whom many develop coagulopathy [1••]. In traumatically injured patients, coagulopathy may already be present on admission of the most seriously injured patients and is associated with a poor outcome [2••]. Existing guidelines advocate early administration of crystalloids and colloids in conjunction with transfusion of red blood cells (RBCs) . Guided by these guidelines, fresh frozen plasma (FFP) and platelets should only be administered when a whole blood volume or more has been substituted, and then according to conventional coagulation analyses.
The current transfusion guidelines are now being challenged, and the concept of hemostatic resuscitation, that is, providing large transfusions of RBCs, FFP, and platelets to critically injured patients in an immediate and sustained manner, has been proposed [4,5]. Furthermore, the introduction of the cell-based model of hemostasis  has renewed the interest in whole blood-based viscoelastical assays for monitoring coagulopathy, instead of the conventional plasma-based coagulation analyses . The purpose of the present review is to survey recent advances in the management of hemorrhage, including monitoring of coagulopathy and transfusion of blood products.
Coagulopathy associated with major blood loss
The dilution of coagulation factors and platelets is a major cause of clinical coagulopathy in massively transfused patients and a result of the recommended aggressive crystalloid resuscitation [8••]. Synthetic colloid resuscitation fluids influence coagulation competence more profoundly than do crystalloids. Hydroxyethyl starch (HES) causes a reduction in the plasma concentrations of coagulation factor VIII and von Willerbrand factor, inhibition of platelet function, and decreased interaction of activated factor XIII with fibrin polymers, effects also seen with the use of dextran . In a rabbit model of uncontrolled hemorrhage, Kheirabadi et al.  demonstrated that hemodilution with Hextend (Hospira Inc. Lake Forest, IL, USA), a HES colloid, and dextran, as opposed to albumin, resulted in hypocoagulation as evidenced by a pronounced reduction in both thrombin generation and clot strength. The reduction in clot strength corresponded to increased bleeding and high mortality, 100% (Hextend), 75% (dextran) vs. 50% (albumin) . Administration of blood products also causes significant dilution due to their storage in preservatives-containing anticoagulants. Thus, even transfusion of RBCs, plasma, and platelets in a 1: 1: 1 ratio results in a solution with a hematocrit of 30%, coagulation factor levels of approximately 60%, and platelet levels around 80 × 109/l .
Hypothermia in massively transfused patients is associated with increased risks of uncontrolled bleeding and mortality [11••]. Platelet dysfunction resulting from hypothermia occurs through multiple mechanisms of which defects in platelet adhesion and aggregation and in thrombin generation on platelets are the most important . Furthermore, there is a 10% reduction in coagulation factor activity for each 1°C drop in core temperature, resulting in prolonged clotting times at temperatures below 33°C . Platelet dysfunction and impaired coagulation enzyme activity are reversible with normalization of temperature to 37°C, highlighting the need to prevent and treat hypothermia aggressively.
Acidemia is induced by hypoperfusion and excess ionic chloride administered during resuscitation [11••]. Acidosis impairs essential parts of the hemostatic process; at a pH below 7.4, platelets change their shape, becoming spheres deprived of pseudopodia. The impaired thrombin generation, secondary to acidosis, is the main cause of coagulopathic bleeding, as exemplified in Martini et al.'s  experiments in which thrombin generation in the propagation phase was inhibited by a pH of 7.1 by as much as 50%. Acidemia also leads to increased degradation of fibrinogen . Importantly, although acidemia can be corrected by administration of buffer solutions, this does not correct the coagulopathy, implying that the acidotic effect is more than simply a physical reduction in protease activity.
Tissue injury, particularly in association with extensive endothelial injury, is associated with consumption of coagulation factors and platelets and hence development of coagulopathy [15••]. Furthermore, there is dysregulation of coagulation attributed to consumption of antithrombin III and increased fibrinolysis due to increased levels of tissue plasminogen activator. A combination of the factors mentioned above, together with dilution, hypothermia, and metabolic acidosis, contributes to the ‘bloody vicious cycle’.
Recently, Brohi et al. [16,17••] described an early acute coagulopathy of trauma occurring before the appearance of the aforementioned traditional causes of traumatic coagulopathy. By analyzing plasma from trauma patients, they reported that tissue injury and hypoperfusion, followed by activation of the anticoagulation thrombomodulin protein C pathway, play central roles in the pathogenesis of acute traumatic coagulopathy characterized by coagulopathy in conjunction with hyperfibrinolysis.
The introduction of the cell-based model of hemostasis emphasizes the pivotal role of platelets for intact thrombin generation, and also highlights the importance of the dynamics of thrombin generation in influencing the quality and stability of the thrombus formed . Consequently, hemostatic assays performed in plasma alone are of limited value, and this explains the finding that activated partial thromboplastin time (APTT) and prothrombin time (PT) do not correlate with clinically relevant coagulopathies or bleeding conditions [18,19]. Instead, it is preferable to employ a hemostatic assay, such as thrombelastography (TEG), which records the viscoelastic changes during coagulation by analysis of whole blood placed in a rotating cup  (Fig. 1). A pin suspended in the blood from a torsion wire records the resistance to motion. Four parameters are routinely reported: reaction time (R) denotes the latency from the time at which the blood is placed in the cup until the clot begins to form, the angle (α) represents the progressive increase in clot strength, the maximum amplitude reflects the maximal clot strength, and lysis reflects clot lysis (Fig. 1).
Our group [20•] demonstrated that TEG thrombus generation correlates with thrombin generation kinetics. Coagulation factor deficiency, thrombocytopenia/thrombocytopathy, or both may result in impaired thrombin formation and, in turn, impaired clot formation. Reduced clot stability, as evaluated by TEG, correlates with clinical bleeding conditions. This was elegantly demonstrated by Plotkin et al. [21••], who reported that, in patients with penetrating trauma, TEG was a more accurate indicator of blood product requirements than PT and APTT. They recommended that TEG, enhanced by platelet count and hematocrit, should be used to guide blood transfusion requirements, and we concur with this recommendation. Furthermore, TEG is the gold standard for identifying hyperfibrinolysis, a significant cause of bleeding in major trauma, ischemia/reperfusion injury, and obstetric calamities [22,23].
The TEG analysis is now validated for routine laboratory use including with the use of the nonphysiologic activator of coagulation, kaolin, rather than with the use of tissue factor . We demonstrated that the different TEG assays showed no significant day-to-day variation, and the coefficient of variance for the TEG parameters investigated was acceptable for clinical practice (5–10%), also when performed on citrated blood samples. Thereby, TEG analyses can be performed in the laboratory and displayed in real-time at the bedside in the operating room, ICU, and trauma center, enabling early correction of coagulopathy by clinicians.
Administration of red blood cells
Lowered hematocrit contributes to coagulopathy. Erythrocytes are important for hemostasis by allowing marginalization of platelets toward the capillary wall and endothelium . In addition, erythrocytes have been shown to modulate the biochemical and functional responsiveness of activated platelets and support thrombin generation . An acute drop in the hematocrit will increase bleeding times, but this can be reversed with RBC transfusion [27••]. The optimal hematocrit for platelet–vessel wall interactions is unknown but may be as high as 35% and is consequently well above the level needed for oxygen delivery [27••].
Ratios of fresh frozen plasma and platelet to red blood cell
During the past 18 months, nine retrospective studies involving more than 2900 trauma patients receiving at least 10 units of RBCs within 24 h of arrival have been published [28,29••,30–32,33•,34–36]. In these studies [28,29••,30–32,33•,34–38,39•], the effect on survival of administration of FFP vs. RBCs or FFP and platelets vs. RBCs has been examined (Table 1). All nine studies demonstrate a survival benefit for the patients who receive more FFP and platelets as part of the hemostatic resuscitation. This was found in both civilian and military settings. Patients receiving a high FFP:RBC or platelet:RBC ratio demonstrated improved survival, with patients receiving both high FFP:RBC and platelet:RBC ratios exhibiting the highest survival rate.
With regard to the optimal ratio of FFP:RBC, conflicting results have been reported. Maegele et al. [29••] showed in German trauma patients that an FFP:RBC ratio higher than 1: 1 was associated with the highest survival rate. On the contrary, Kashuk et al.  reported that patients receiving an FFP:RBC ratio of 1: 2–1: 3 demonstrated the highest survival rate, and that a higher ratio was not associated with better outcomes but instead might actually be harmful. An important limitation on the observations reported by Kashuk et al.  is that the group receiving a high FFP:RBC ratio included only 11 patients, accounting for just 8% of the patients included in the study. It can be concluded, however, that an FFP:RBC ratio higher than 1: 2 is associated with improved survival rates as compared with a ratio lower than 1: 2, as is reported in five of the studies [28,30–32,33•]. Furthermore, it appears that when comparing different FFP:RBC ratios higher than 1: 2, the patients receiving the most plasma exhibit the highest survival rates [29••,34].
Importantly, not only coagulation factors but also platelets are pivotal for hemostasis, and an association between thrombocytopenia and increased postoperative bleeding and increased mortality has previously been reported [5,40]. Four of the studies (Table 1) reported on the effects of platelet transfusion [33•,34–36], and all of them demonstrated improved survival in the group of patients receiving most platelets. Holcomb et al. [33•] demonstrated that the highest survival rate occurred in patients who received both high platelets:RBC and high FFP:RBC ratios. In fact, when comparing platelets:RBC and FFP:RBC ratios and survival rates, patients receiving a high platelets:RBC ratio displayed the highest survival rate. This is further corroborated by Stinger et al.  who reported, by multiple regression analyses, that platelet transfusion is independently associated with survival.
Massive transfusion protocols
Cotton et al.  implemented a trauma exsanguination protocol (TEP) involving 10 units of RBCs, four units of FFP, and two units of apheresis platelets for trauma patients. This protocol was used to evaluate 211 trauma patients, of whom 94 received TEP and 117 were historic controls. TEP patients intraoperatively received more RBCs (16 vs. 11), FFP (eight vs. four), and apheresis platelets (two vs. one) than the controls and displayed lower 30-day mortality (51 vs. 66%). After controlling for age, sex, mechanism of injury, trauma injury severity score (TRISS), and 24-h blood product usage, a 74% reduction in the odds of mortality was observed among patients in the TEP group. Overall blood product consumption adjusted for age, sex, mechanism of injury, and TRISS was also significantly reduced in the TEP group. Gunter et al.  evaluated an additional 48 TEP-treated trauma patients together with those investigated by Cotton et al.  and demonstrated that the ratio of FFP to RBCs was an independent predictor of 30-day mortality when controlling for age and TRISS (odds ratio 1.78, 95% confidence interval 1.01–3.14).
Our group investigated 832 consecutive massively transfused patients 2 years prior to and 2 years after implementation of hemostatic control resuscitation (HCR) [39•]. This protocol encompassed transfusion packages made up of five units of RBCs, five units of prethawed FFP, and two units of buffy coat platelets (produced from four buffy coats) to be administered to patients with uncontrollable bleeding. When hemodynamic control was established, the transfusion therapy was directed by TEG analyses (Table 2). The HCR group had higher FFP:RBC ratio and received more platelets within 24 h of admission as compared with controls, and the 30 and 90-day mortality was significantly reduced following HCR implementation vs. controls (20 vs. 31% and 22 vs. 35%), corroborating the results from the trauma setting.
Interestingly, Cotton et al. [41••] recently reported on the same cohort previously described, with inclusion of a total of 264 trauma patients, and found that not only was the 30-day survival rate higher in the TEP group than in controls but also that the incidence of severe sepsis or septic shock and multiorgan failure were lower in TEP patients (9 vs. 20% and 16 vs. 37%, respectively).
Recombinant factor VIIa
Recombinant factor VIIa (rFVIIa) acts in supraphysiological doses by enhancing thrombin generation on activated platelets independent of factor VIII and IX and is currently approved for episodes of severe hemorrhage or perioperative management of bleeding in patients with congenital factor VII deficiency and hemophilia A or B with inhibitors . Since the first case report of rFVIIa use in trauma was published in 1999 , there has been substantial off-label use of rFVIIa for the management of various nonhemophilic bleeding conditions. To date, 17 randomized controlled trials have been reported concerning different bleeding conditions and none have reported a survival benefit in the rFVIIa-treated arms . In June 2008, Novo Nordisk discontinued a phase-3 clinical trial with NovoSeven for the treatment of bleeding in patients with severe trauma (http://www.drugs.com/clinical_trials/novo-nordisk-discontinues-phase-3-clinical-trial-novoseven-trauma-4741.html).
However, in patients with massive uncontrolled blood loss, Spinella et al.  reported a case–control study from the Iraqi combat setting in massively transfused patients with an injury severity score above 15. This study demonstrated reduced 30-day mortality in rFVIIa-treated patients as compared with controls (31 vs. 51%). Furthermore, Berkhof and Eikenboom  recently reported on 32 patients with uncontrolled massive blood loss, demonstrating a significant reduction in transfusion requirements after administration of rFVIIa, when compared with before administration, and a 56% survival. Importantly, administration of rFVIIa should be preceded by administration of platelets and fibrinogen to ensure optimal conditions for the rFVIIa to act. Off-label use of rFVIIa, however, is still considered controversial and should be used only with caution and sound clinical judgment.
Implementation of more aggressive hemostatic resuscitation strategies in massively bleeding patients seems reasonable on the basis of this review. It is intriguing that increased amounts of plasma and platelets result in improved survival, and that this is the recommended therapy when TEG is used to guide transfusion therapy in massively bleeding patients. This indicates that whole blood viscoelastical assays may be preferable for monitoring coagulopathy in massive bleeders and supports a paradigm shift in transfusion medicine regarding monitoring and treatment of massive bleeders.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 528).
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