Fresh frozen plasma and platelets

Classically, resuscitation in hemorrhage has been centered on the administration of crystalloids and packed red blood cells (PRBCs). Use of other blood products like fresh frozen plasma, cryoprecipitate, and platelets was traditionally withheld until there was laboratory evidence of developing coagulopathy (eg, platelet count <50,000/mm³, fibrinogen <100–150 mg/dL, prothrombin time (PT), or activated partial thromboplastin time >1.5 × normal).

These transfusion guidelines fail to prevent early coagulopathy in massive bleeding. Patients with crystalloid/PRBC-based resuscitation will frequently develop dilution of clotting factors and platelets, leading to dilutional coagulopathy. Massive crystalloid resuscitation may further worsen bleeding prior to achieving the surgical control of hemorrhage by increasing intravascular hydrostatic pressures and dislodging fresh clots at sites of endothelial injury.

Excessive amounts of crystalloids have been associated with third spacing, leading to cerebral, cardiac, and pulmonary edema. Third spacing from massive crystalloid-based resuscitation may also worsen hemodynamics and renal perfusion by increasing intraabdominal pressures, leading to abdominal compartment syndrome. Furthermore, recent evidence suggests that excessive administration of crystalloids in the setting of acute kidney injury (not uncommon in massive hemorrhage) results in interstitial kidney edema with renal vein obliteration delaying the recovery of kidney function. Chlorine-rich fluids (eg, 0.9% saline) worsen kidney function because chloride induces renal vasoconstriction. Recent evidence advocates the use of balanced crystalloid solutions such as lactated Ringers and Plasmalyte.

Prior to surgical control of hemorrhage, permissive hypotension with systolic blood pressures between 80 and 100 mm Hg may be optimal to limit ongoing blood loss. Permissive hypotension may be considered in patients with postpartum hemorrhage. However, there are no data regarding permissive hypotension prior to delivery of the fetus, when the risks and benefits need to take into account the effect on uterine perfusion.

Early coagulopathy may occur prior to hemodilution and before the consumption of clotting factors takes place. This mechanism of early coagulopathy has mainly been studied in trauma; however, obstetrical hemorrhage may share some of the mechanisms involved. Hypoperfusion results in an up-regulation of thrombomodulin receptors on endothelial cells.

These receptors interact with thrombin, leading to the activation of the protein C pathway. Protein C will irreversibly inhibit factors Va and VIIIa and enhance fibrinolysis through inhibition of plasminogen activator inhibitor 1. Similarly, endothelial ischemia results in increased production of tissue plasminogen activator, resulting in increased fibrinolysis.

Increased fibrinolytic activity has been described in obstetrical hemorrhage secondary to uterine atony, placental abruption, and accretism. Early use of antifibrinolytic agents (eg, epsilon-aminocarpoic acid or tranhexamic acid) has been shown to decrease bleeding and mortality among trauma victims. Following placental separation, the fibrinolytic pathway is activated for up to 10 hours into the postpartum period.

Hemostatic resuscitation has emerged as an option to overcome the previously described shortcomings. The key concept of this approach is to limit the administration of crystalloids and instead make blood products the cornerstone of resuscitation.

In hemostatic resuscitation, packed red blood cells are administered in a 1:1:1 ratio with fresh frozen plasma (FFP) and platelets. The administration of these products is given, regardless of laboratory values. Theoretically, clotting factor dilution and third spacing are minimized with this approach. One unit of platelets will increase the platelet count by 5000–10,000/mm ³ . When administering platelets, the typical dose used is 1 U per 10 kg of weight. One unit of FFP contains all clotting factors including 2 g of fibrinogen for each 1000 mL. One unit of FFP (200–250 mL) increases serum fibrinogen by 10 mg/dL.

Overall, the evidence behind the use of hemostatic resuscitation is limited. Retrospective studies have demonstrated absolute mortality reductions between 15% and 62% with the use of high ratios of FFP:PRBC (eg, 1:1). A limitation of the available literature is the presence of survival bias. On average, the median time for obtaining the first unit of PRBC is 18 minutes, as opposed to more than 1 hour for fresh frozen plasma (needs to be thawed).

It is likely that the patients who received fresh frozen plasma were not as sick as those who died before the fresh frozen plasma was available. Patients’ ability to survive until fresh frozen plasma was available to be included in the group who received it may have biased the analysis in favor of high FFP:PRBC ratios. A limited number of studies have specifically addressed the survivorship bias in high FFP:PRBC studies. When early deaths were excluded, no survival benefit for higher ratios was noted.

A recent randomized clinical trial among patients with severe trauma-associated hemorrhages found no difference in mortality at 24 hours or 30 days when comparing the use of plasma, platelets, and red cells at a 1:1:1 ratio to a 1:1:2 ratio. In a subgroup analysis, patients assigned to the 1:1:1 ratio had lower deaths from exsanguination in the first 24 hours, and more patients in the 1:1:1 ratio achieved hemostasis. Importantly, despite more use of plasma and platelets in the 1:1:1 ratio group, there was no difference in adverse outcomes, including sepsis, acute kidney injury, acute lung injury, febrile transfusion reactions, or multiorgan failure. This latest trial provides the best available evidence to date favoring the use of hemostatic resuscitation.

Recombinant activated factor VII

Early administration of recombinant activated factor VII (rFVIIa) was typically included in massive transfusion protocols if bleeding persisted after administration of a predetermined number of blood products. rFVIIa is licensed for use in patients with hemophilia and inhibitory alloantibodies against factors VIII or IX. It has increasingly been used for off-license indications, including trauma, heart surgery after cardiopulmonary bypass, warfarin reversal, and obstetrical hemorrhage. Despite having a very short half-life, concerns about thrombotic events as a complication are real.

A recent study found an increased risk of arterial thrombosis among recipients of recombinant activated factor VII. rFVIIa is not a first-line treatment for bleeding, and it is effective only after major sources of bleeding have been controlled. The use of this product should be combined with best practice use of blood products. Ideally, the patient should have a platelet count >50,000/mm³, fibrinogen >50–100 mg/dL, temperature >32°C (pH > 7.2), and normal ionized calcium prior to administration.

Randomized controlled trials addressing the use of rFVIIa in massive hemorrhage have found an overall reduction in transfusion requirements or blood loss, but none has reported a survival benefit. In obstetrics, the available evidence is mostly from case reports and case series. In cases of amniotic fluid embolism, the use of this agent has been associated with increased mortality. At this time, given the well-known adverse effects of recombinant activated factor VII, its extremely high cost, and its lack of survival benefit, it is difficult to justify the routine use of this agent in massive transfusion protocols. The use of other pharmacological approaches with a more favorable profile, including tranexamic acid (TXA), fibrinogen concentrates, and prothrombin complex concentrates, may be preferable.

Recombinant activated factor VII

Early administration of recombinant activated factor VII (rFVIIa) was typically included in massive transfusion protocols if bleeding persisted after administration of a predetermined number of blood products. rFVIIa is licensed for use in patients with hemophilia and inhibitory alloantibodies against factors VIII or IX. It has increasingly been used for off-license indications, including trauma, heart surgery after cardiopulmonary bypass, warfarin reversal, and obstetrical hemorrhage. Despite having a very short half-life, concerns about thrombotic events as a complication are real.

A recent study found an increased risk of arterial thrombosis among recipients of recombinant activated factor VII. rFVIIa is not a first-line treatment for bleeding, and it is effective only after major sources of bleeding have been controlled. The use of this product should be combined with best practice use of blood products. Ideally, the patient should have a platelet count >50,000/mm³, fibrinogen >50–100 mg/dL, temperature >32°C (pH > 7.2), and normal ionized calcium prior to administration.

Randomized controlled trials addressing the use of rFVIIa in massive hemorrhage have found an overall reduction in transfusion requirements or blood loss, but none has reported a survival benefit. In obstetrics, the available evidence is mostly from case reports and case series. In cases of amniotic fluid embolism, the use of this agent has been associated with increased mortality. At this time, given the well-known adverse effects of recombinant activated factor VII, its extremely high cost, and its lack of survival benefit, it is difficult to justify the routine use of this agent in massive transfusion protocols. The use of other pharmacological approaches with a more favorable profile, including tranexamic acid (TXA), fibrinogen concentrates, and prothrombin complex concentrates, may be preferable.

Fibrinogen and cryoprecipitates

In the setting of massive hemorrhage, fibrinogen is the first clotting factor to fall to critically low levels. Fibrinogen plays a pivotal role in clotting by serving as the substrate for thrombin to generate fibrin and also by interacting with the glycoprotein IIb/IIIa on the platelet surface. Achieving specific fibrinogen levels is now considered an important target during massive transfusion. Whereas previous guidelines recommended maintaining a level above 100 mg/dL during a bleeding episode, currently it is recommended that levels above 150–200 mg/dL be targeted.

During normal pregnancy, fibrinogen levels increase to values as high as 400–500 mg/dL so that low values may represent a more severe coagulopathy compared with nonpregnant individuals. In the setting of obstetrical hemorrhage, a serum fibrinogen level below 200 mg/dL had a positive predictive value for progression to severe hemorrhage of 100%. It is, therefore, reasonable to target a fibrinogen level of at least 150–200 mg/dL during obstetrical hemorrhage.

In the United States, most of the fibrinogen replacement is done in the form of cryoprecipitates (100 mL of cryoprecipitate contain approximately 2 g of fibrinogen). Each unit of cryoprecipitate will increase the serum fibrinogen by 10 mg/dL. The usual adult dose of cryoprecipitate is 10 U, which is expected to raise the serum fibrinogen by 100 mg/dL. Disadvantages with the use of cryoprecipitate include the necessity to thaw prior to use and the risk of virus transmission.

Fibrinogen concentrates have emerged as an extremely effective agent in recent years and have been used in trauma, cardiovascular surgery, and obstetrics. The safety profile of this product is favorable because viral inactivation and removal of multiple antigens and antibodies is part of the manufacturing process. Fibrinogen concentrates are stored at room temperature, are available for immediate use, and come in small volumes with high fibrinogen concentrations (2 g of fibrinogen in 100 mL). The recommended initial dose is 2–3 g intravenously with subsequent doses adjusted according to serum fibrinogen levels.

Multiple case reports and case series attest to the efficacy of fibrinogen concentrates in the management of obstetrical hemorrhage. Similarly, the use of fibrinogen concentrates in trauma victims with severe hemorrhage has been effective, with a significant decrease in blood product requirements.

Most clinical data to date suggest that fibrinogen concentrates play a key role as a hemostatic agent resulting in reduced requirements of allogeneic blood product transfusions without evidence of harmful effects. We believe that fibrinogen concentrates will play a major role in the management of obstetrical hemorrhage in the near future. Unfortunately, fibrinogen concentrates are not yet widely available in the United States.