Validated algorithms have been developed for predicting whether a patient is suffering from massive blood loss and requires inclusion in a massive transfusion protocol (MTP).10 If transfusion is urgent, we request 0 negative red cell concentrate and AB plasma, until cross-testing is performed.

The concept of MTP is recent,11 and such protocols are advised in patients with massive bleeding who present the lethal triad of acidosis, hypothermia and coagulopathy. The aim is to treat the patient early and aggressively with blood products, in order to avoid exsanguination and coagulopathy. MTP requires coordination with the blood bank, core laboratory and intensivist for requesting tests referred to coagulation, hemoglobin and platelets. In MTP, the patient is administered equivalent amounts of the three blood products (Table 2).

Conventional resuscitation with large volumes of fluids can lead to dilutional coagulopathy–the latter in turn being worsened by the hypothermia and acidosis that accompany trauma. In order to deal with this problem, the United States Army's Institute of Surgical Research conference12 in 2005 proposed a transfusion strategy involving immediate administration of the three blood products in massive bleeding secondary to trauma (Table 3).

Since then, transfusion strategies have been introduced with higher plasma and platelet to red cell concentrate ratios, simulating whole blood. Although some non-randomized observational studies have found these ratios to improve survival among patients with massive bleeding,13,14 other recent studies have been unable to confirm these findings.15,16

Despite the disparity of published data and the increase in resource consumption associated with the use of such high ratios, MTP has been accepted in many centers in North America and Europe. In this sense, the Canadian Blood Services reported a 50% increase in the demand for AB plasma between the years 2007 and 2009.17

While acknowledging these data, the European massive transfusion guideline of 2007 gave no specific recommendations referred to the mentioned ratio, in the same way as the more recent guides of the European task force18 and the American Association of Blood Banks,19 which recommend early intervention with FFP, though without establishing ratios.

A recent Scandinavian study15 presented as main finding the observation that the change in transfusion strategy (in the context of a pre- and post-intervention retrospective study), referred to more aggressive and earlier administration of plasma and platelets, exerts no influence upon the survival of patients with bleeding due to trauma–this being confirmed by a multivariate analysis in patients subjected to massive transfusion, concluding that the devastating effects of trauma cannot be reverted by this change in strategy alone.

Another recent systematic review on this same subject compared high and low transfusion ratios, noting that most studies report favorable results with high ratios. However, the presence of screening error was evidenced, which could affect the results obtained. The authors concluded that there is not enough evidence supporting indication of the fixed 1:1:1 ratio.20

At present, a priority concern is the conduction of controlled and randomized clinical trials designed to document the risk-benefit ratio of the different transfusion ratios in massive bleeding9.

Coagulopathy is the most feared complication in massive bleeding. Patients with severe trauma and also those subjected to major surgery suffer alterations in the integrity of the vascular endothelium. These situations give rise to coagulopathy, of a multifactorial origin, and in which all the coagulation factors are deficient to one degree or other. When such coagulopathy is accompanied by hypothermia and acidosis, the patient prognosis is seriously worsened (lethal triad), though coagulopathy in itself constitutes an independent mortality factor.

Two phases are recognized in coagulopathy associated to massive bleeding: primary coagulopathy, which is of early onset, and secondary coagulopathy, which manifests in a later stage. Traditionally, coagulopathy was always believed to be a late event, though it is now known that coagulation disorders can manifest very early, from as soon as the time of patient admission to hospital. Primary coagulopathy is related to tissue factor exposure, thrombin generation, and the activation and consumption of protein C–leading to the very early development of disseminated intravascular coagulation and fibrinolysis. This situation is also referred to as trauma-induced early coagulopathy, and its presence implies a significant increase in mortality.21,9

In contrast, secondary coagulopathy is of later onset and is related to the loss of coagulation factors and the dilution of the existing factors. Both coagulopathy phases manifest as the presence of nonsurgical bleeding (non-massive bleeding from multiple locations, and with difficult control). The laboratory diagnosis includes the following parameters: prolongation of prothrombin time (PT) and of activated partial thromboplastin time (aPTT) to >1.5 times the control value, an international normalized ratio (INR) of >1.5, a platelet count of <50×109/l, and fibrinogen values of <0.5–1g/l. Fibrinolysis and platelet dysfunction manifest very early.22

The concept of primary coagulopathy is beginning to prevail over that of secondary coagulopathy. As a result, the current recommendations suggest immediate management of primary coagulopathy, with the early transfusion of large amounts of fresh plasma and platelets, avoiding hypothermia and acidosis. Both coagulopathy phases can coincide in one same patient. A recent study23 in patients with serious TBI confirmed a high prevalence of early and late coagulopathy, and both were independently correlated to a poor clinical outcome. These data suggest that coagulopathy must be monitored and corrected in its most incipient or early phase.

The principal efforts referred to the transfusion of blood products and the use of other hemostatic interventions in general begin when the patient is admitted to a third level hospital center. Consequently, the time elapsed from injury to admission is a critical factor, particularly in situations of hemorrhagic shock. Conventional transfusion is not usually performed at the site of the accident. The best strategy referred to coagulopathy secondary to massive bleeding remains the subject of debate.24

The only accepted indication of red cell transfusion is for increasing tissue oxygenation in anemic patients with tissue oxygen deficiency.2 Prescription is made in the form of 220–400ml units of red cell concentrate depleted of leukocytes and stored in the blood bank for up to 42 days. One red cell concentrate unit increases hemoglobin by 1g/dl (or hematocrit by 3%).25 The optimum hematocrit for ensuring good oxygen transport and preventing dilutional coagulopathy in massive bleeding is not known, but is probably in the range of 35%. More stable young patients with a good cardiopulmonary reserve can tolerate normovolemic anemia to a hemoglobin concentration of 8g/dl. Older patients or individuals with a poorer cardiopulmonary reserve require hemoglobin 9–10g/dl.

Frequent measurement is required of hemoglobin and hematocrit. Initially, the hemoglobin values may be normal, despite important blood loss. Good communication with the laboratory and Department of Hematology is needed. It is particularly important to inform the laboratory of the urgency with which the blood is needed: immediately, in 20min, or in the next hour. If the need is immediate and the blood group is not known, the laboratory must supply group 0 negative red cell concentrates, without cross-testing. Women of child-bearing potential must receive group 0 negative Rh D negative units. In other cases group 0 Rh D positive blood is acceptable, if Rh D negative units are not available. Definitive blood grouping should take no more than 10min, after which isogroup blood transfusion is indicated.

A pool of platelets contains approximately 200ml of platelet concentrate, obtained from 6 donors. These concentrates are stored in the blood bank at 22°C for up to 5 days. ABO group compatibility is not necessary. A platelet concentrate unit increases the platelet count by approximately 5–10×109/l. Although classically the threshold for deciding platelet transfusion has been 50×103/μl, the tendency in recent years has been to administer a platelet unit simultaneously with a red cell concentrate and plasma (1:1:1 ratio) in massive bleeding.14,15,20,25 In patients with platelet dysfunction (secondary to antiplatelet medication, aspirin and/or clopidogrel, for example), additional platelet transfusions may be needed, despite the presence of a normal platelet count.

This section considers those drugs which can be useful in reducing or controlling bleeding in patients with massive hemorrhage. However, their high cost and the lack of studies consistently documenting their efficacy limit the generalized clinical application of such substances.

Antifibrinolytic agents inhibit the plasminogen-plasmin fibrinolytic system, preventing blood clot lysis, which can lead to a decrease in bleeding. Their efficacy has been well documented in surgical patients, including patients subjected to heart surgery and liver transplantation.31 A recent randomized, double-blind, placebo-controlled trial32 has evaluated the use of tranexamic acid administered early in the first 8h after trauma in the form of an intravenous dose of 2g (1g in an initial bolus dose and 1g in perfusion during 8h). This treatment was seen to decrease both global mortality and mortality attributable to bleeding in polytraumatized patients. The mechanism by which tranexamic acid reduces mortality may be related to an antiinflammatory effect mediated by plasmin.

Since this is the first time a drug has been shown being able to reduce the mortality of traumatic hemorrhagic shock, and considering the large number of fatalities due to this reason, its compassionate use has been proposed until the above indication is included in the Summary of Product Characteristics.33,34

Recombinant activated factor VII is being used off label (i.e., indicated outside the Summary of Product Characteristics) for the treatment of massive bleeding refractory to conventional therapy with blood products, in the absence of solid supporting scientific evidence.35 Before its administration, the patient acidosis and hypothermia must be corrected, attempting to maintain fibrinogen levels of ≥150mg/dl, a platelet count of >50,000mm–3 and a hematocrit of >24%.25

In polytraumatized patients with incoercible bleeding, a starting dose of 200μg/kg is advised, followed by two doses of 100μg/kg, 1–3h after the first dose–though the efficacy of such treatment has only been shown in closed traumatisms.36 In perioperative hemorrhage, the recommended dose is 90μg/kg, which can be repeated if the bleeding persists.

Recombinant activated factor VII has been used in application to incoercible bleeding related to trauma and in perioperative hemorrhage. However, rFVIIa can give rise to thromboembolic phenomena in over 6% of the cases.37 The main adverse effects are related to the presence of tissue factor abnormally exposed in the diseased endothelium (atheroma plaques)–with the consequent risk of arterial or venous thrombosis. Thrombotic complications are more frequent in arterial territories than in veins, and include non-hemorrhagic cerebrovascular stroke and acute coronary syndrome. The venous complications in turn include deep venous thrombosis and pulmonary thromboembolism.38

A recent metaanalysis39 including 5 observational studies and a controlled clinical trial40 evaluated the use of rFVIIa in refractory hemorrhage in heart surgery patients, and documented a statistically nonsignificant increase in the incidence of cerebrovascular events. More controlled clinical trials are needed to determine the risk-benefit ratio of the administration of rFVIIa in patients with massive bleeding. Its high cost, about 4000 euros (mean dose 90μg/kg), limits the use of this treatment.

Fibrinogen is a soluble plasmatic glycoprotein with a molecular weight of 340kDa, produced in the liver, and with a plasma concentration of between 2 and 3.5g/l. The half-life is between 72 and 120h. As coagulation factor I, fibrinogen is the precursor of fibrin and the physiological substrate of three enzymes: thrombin, FXIII and plasmin. Although the minimum levels needed to reduce bleeding due to coagulopathy are not known, the European guideline18 recommends the maintenance of levels of 1.5–2g/l.

Fibrinogen is also the coagulation factor that most quickly reaches critical levels in massive bleeding. When its levels drop to under 1g/l, fresh plasma, fibrinogen concentrate or cryoprecipitate must be administered. Early correction to optimum levels (2–3g/l) can reduce mortality among trauma patients.28,41

The transfusion of FFP may be insufficient to increase the plasma fibrinogen levels (30ml/kg of plasma increase fibrinogen by 1g/l; a patient weighing 80kg would need 2400ml of FFP). In contrast, the administration of fibrinogen concentrate is more effective in increasing the plasma levels. A high fibrinogen/red cell concentrate ratio has been associated with a decrease in mortality in war wound patients. Levels of over 3g/l can even compensate a low platelet count.28

There is growing scientific evidence that the early use of fibrinogen concentrate reduces bleeding and the transfusion of blood products after a major surgery, without an associated increase in thrombotic complications.42–44 Although restoring the levels of this factor seems to be advantageous for the control of massive bleeding secondary to major surgery or trauma, the choice among FFP, cryoprecipitate or fibrinogen concentrate remains the subject of debate.25

Prothrombin complex concentrate contains variable amounts of coagulation factors II, VII, IX and X, obtained from a plasma pool of at least 1000 donors. Depending on its factor VII concentration, PCC is divided into 3-factor PCC (low concentrations of factor VII) or 4-factor PCC (high concentrations of factor VII). PCC contains a 1000-fold higher concentration of coagulation factors than FFP. In fact, one FFP unit (about 250ml) contains only 0.5–1U/ml of all the plasma factors.25

PCC is only indicated in patients with massive bleeding involving a prolongation of the coagulation times (INR>1.5) and overdosed with vitamin K antagonists.26 However, observational studies have been published including polytransfused patients, patients with coagulopathy, incoercible bleeding, and patients not administered vitamin K antagonists.24,45

PCC has been used in perioperative bleeding unrelated to the administration of vitamin K antagonists. In 38 patients with perioperative bleeding, the administration of 2000IU of PCC decreased INR from 1.7 to 1.4, arresting bleeding in 96% of the patients with diffuse microvascular hemorrhage (due to coagulopathy) and in 36% of the patients with surgical bleeding.34 The administration of 1500IU of PCC reduced the transfusion rate in 16 patients subjected to heart surgery, with incoercible bleeding not previously treated with vitamin K antagonists.35 This suggests that the administration of PCC may be useful for the treatment of perioperative bleeding unrelated to the administration of vitamin K antagonists.

Lastly, a single observational study explored the efficacy of PCC in improving coagulation, and in reverting or preventing bleeding in 22 patients with severe liver failure. The INR value normalized 10minutes after infusion, and the clinical response (prevention, reduction or cessation of bleeding) was considered very good or good in 100% of the patients.46 PCC could prove useful in application to bleeding or in preventing bleeding in patients with a deficiency of liver-dependent factors secondary to acute liver failure (Table 5).

In experimental animal models in which coagulopathy was induced by exsanguination and polytransfusion, the administration of PCC decreased hemorrhage and the transfusion needs.47

Although the initial results are promising, the studies documenting the efficacy of PCC in controlling coagulopathy unrelated to the administration of vitamin K antagonists are few and of an observational nature. As a result, the generalized use of PCC cannot be recommended, outside its established indication for reverting the antagonistic effect of vitamin K.

The main adverse effect of PCC is venous or arterial thrombosis, particularly in patients with liver disease, newborn infants, or individuals requiring very high or repeated PCC doses. Nevertheless, the described adverse effect rates are very low, and moreover no clear cause-effect relation has been established.

The mean cost per vial of 4-factors PCC is about 1000 euros.