Massive bleeding is classically described as loss of 1 blood volume in 24 hours. In the context of these recommendations, we should consider greater loss of blood volumes, such as loss of 50% blood volume in less than 3 hours. Under these conditions, administration of blood products would precede the administration of rFVIIa.
General recommendations
Recommendation 1. Every attempt should be made to control bleeding by conventional means. rFVIIa should not replace and/or delay surgery or any other methods used to control the source of bleeding, such as angiography with embolization. Grade E
Rationale 1. rFVIIa will be effective only once sources of major bleeding (such as open blood vessels) have been closed. Once major bleeding from damaged vessels has been stopped, it may be helpful to induce coagulation in areas of diffuse bleeding and oozing.
Recommendation 2. Traditional use of blood products, including RBCs, platelets, FFP, and cryoprecipitate/fibrinogen, should not be replaced by rFVIIa. Grade E
Rationale 2. rFVIIa is not a first-line treatment for bleeding. The focus of treatment is still replacement therapy with blood products such as RBCs, FFP, platelets, and cryoprecipitate/fibrinogen. rFVIIa should be considered only if first-line treatment with a combination of blood products and surgical approaches fails to control bleeding. However, it should be remembered that for rFVIIa to promote coagulation, sufficient levels of platelets and fibrinogen are required.
Recommendation 3. Every effort should be made to reduce the effects of, or to achieve the correction of, factors that may interfere with coagulation, including hypothermia, severe acidosis, low hematocrit, and hypocalcemia. An attempt to reverse the effects of any anticoagulant therapy should be made when possible. Grade E
Rationale 3. Hypothermia and coagulopathy in trauma are currently poorly understood; in general, the greater the degree of hypothermia, the greater the risk of uncontrolled bleeding. When severe injury is associated with hypothermia and acidosis, mortality rates of up to 100% have been reported. The effects of hypothermia include altered platelet function, impaired coagulation factor function (a 1°C decrease in temperature is associated with a 10% decrease in function), enzyme inhibition, and fibrinolysis [
20,
21]. Body temperatures below 34°C compromise blood coagulation, but this has been observed only when coagulation tests (prothrombin time [PT] and activated partial thromboplastin time) are performed at the low temperatures seen in patients with hypothermia, and not when assessed at 37°C (as is routine practice for such tests). Although Meng and colleagues [
22] have shown that correction of hypothermia is not necessary for the proper functioning of rFVIIa, body temperature should be restored to as near physiological levels as possible, because even small reductions in temperature can result in slower coagulation enzyme kinetics [
23].
In addition, coagulation disorders are aggravated by acidosis, caused by inadequate tissue oxygen supply. Moreover, hypocalcemia is frequently present in severely injured patients [
24] and may require the administration of intravenous calcium, followed by frequent assessment to control serum levels of ionized calcium.
Recommendation 4. If major bleeding persists despite the above steps, the use of rFVIIa should be considered. To ensure maximal rFVIIa efficacy, attempts should be made to achieve the following: platelets more than 50,000 × 109/l; fibrinogen 0.5 to 1.0 g/l; pH ≥ 7.20; hematocrit more than 24%. Grade E
Rationale 4. rFVIIa acts on the patient's own clotting system. To ensure the formation of a stable clot, fibrinogen levels will need to be maintained [
25,
26]. Furthermore, at pharmacological (that is, supraphysiological) doses, rFVIIa triggers the thrombin burst through direct binding to activated platelets; sufficient platelets must therefore be available. A reduction in platelet count also leads to impaired thrombin generation [
27]. A recent study has shown that a pH of less than 7.10 will substantially reduce rFVIIa activity [
22].
Recommendation 5. Before administering rFVIIa, the patient, or the patient's next of kin, should be informed about the type of treatment that they are receiving. Grade E
Rationale 5. Because rFVIIa is not approved for any of the indications discussed in this publication, the patient's next of kin should be informed that rFVIIa is being used outside the currently approved indications (off-label use).