CLINICAL OBSTETRICS AND GYNECOLOGY Volume 53, Number 1, 196208 r 2010, Lippincott Williams & Wilkins

Blood Product Replacement for Postpartum Hemorrhage

ANDREA J. FULLER, MD and BRENDA A. BUCKLIN, MD Department of Anesthesiology, University of Colorado at Denver Health Sciences Center, Aurora, Colorado
Abstract: Hemorrhage requiring blood transfusion is a common occurrence in obstetrics. This article reviews each step in the transfusion process, including laboratory preparation of blood, indications for various blood components, complications of blood transfusion, massive transfusion, and alternatives to homologous blood. Current thinking regarding transfusion-related acute lung injury, transfusion-related immunomodulation, early use of plasma for massive transfusion, and the use of adjuvant agents such as activated recombinant factor VII are also discussed. Key words: hemorrhage, blood transfusion, rFVIIa, massive transfusion, cell salvage

tration, including alternatives to banked blood, new thinking about the complications of banked blood, and the pharmacologic treatment of hemorrhage.

Preparing for Transfusion

If blood transfusion is required, the administration of type specific, crossmatched, blood is preferred. The initial step in this process, the Type and Screen, allows administration of typespecific blood and identifies patients who may be difficult to crossmatch due to antired blood cell (RBC) antibodies. First, the patients ABO type and Rh factor status is determined from a blood sample. To do this, the patients blood is mixed with antibodies that react with A, B, or Rh antigens on the patients erythrocytes. If antibodies are present, agglutination occurs. Blood type confirmation is accomplished by mixing the patients blood with RBC containing A or B antigens. When a patients own RBC does not contain A and/or B antigens, she will have antibodies
/ VOLUME 53 / NUMBER 1 / MARCH 2010

Hemorrhage requiring blood transfusion occurs in up to 1.6% of obstetric cases and is one of the leading causes of death.1 Because blood product administration is relatively common in obstetrics, care providers must understand indications for and complications associated with blood product replacement. This chapter will discuss the current and practical information pertaining to blood product adminisCorrespondence: Andrea J. Fuller, MD, Academic Bldg 1, 12631 E. 17th Ave, Aurora, CO. E-mail: Andrea. Fuller@ucdenver.edu
CLINICAL OBSTETRICS AND GYNECOLOGY

196 | www.clinicalobgyn.com

Blood Product Replacement to these antigens and the cells will agglutinate.2 For example, type O blood will agglutinate when mixed with cells containing A and B antigens, whereas type AB blood will not agglutinate with either antigen. Next, the blood is screened for common antibodies. To do this, the recipients blood is mixed with commercially available antigens. If antibodies are present, RBC agglutination or hemolysis is observed. The final step in obtaining crossmatched blood is to mix the patients blood with the donors to mimic the transfusion. This serologic crossmatch identifies antibodies in the Kell, MN, Kidd, and Duffy groups.2 It also can identify recipient antibodies present in such low amounts that they elude the initial antibody screen. Although institutional variation exists, the type and screen can take up to 45 minutes and crossmatching may take an additional 15 minutes.2 A routine crossmatch is not necessary for uncomplicated parturients.3 The decision to crossmatch blood or merely order a type and screen should be based on the patients history and risk for hemorrhage. Patients at high risk for hemorrhage include but are not limited to those with a history of postpartum hemorrhage or placenta previa, as well as those with inherited or acquired coagulation disorders. These high risk patients should probably have type specific, crossmatched blood available before cesarean or vaginal delivery, time permitting. If the patient requires transfusion emergently and type specific, crossmatched blood is unavailable, type O, Rh negative, blood can be given. Administration of Rh negative blood is important in the obstetric population as sensitization can occur with the administration of Rh positive blood and may affect future pregnancies. Once a patient has received large amounts of type O blood, she is at risk for hemolysis when type-specific

197

blood is given due to the passive acquisition of anti-A and anti-B antibodies. The American College of Obstericians and Gynecologists and the American Society of Anesthesiolgists (ASA) Task Force on Obstetric Anesthesia state in their clinical management guidelines that every labor and delivery ward should be prepared to manage hemorrhagic emergencies.1,3 Blood transfusion equipment such as hand-inflated pressure bags, an automatic rapid infusion system, and a fluid warmer should be immediately available.2 Resources vary among facilities and it is the responsibility of the clinician to know the logistics of equipment availability, blood transport, and transfusion before an emergency. Obtaining adequate intravenous access is one of the most important clinical goals in patients at risk for hemorrhage. Short, large bore peripheral IVs are preferred because flow through the cannula is directly proportional to the fourth power of the radius and inversely proportional to the length. Large bore peripheral IVs are usually adequate and the placement of a central line may divert attention and resources in a hemorrhagic emergency. If central venous access is obtained, a 9-French introducer sheath is preferred to a longer catheter (such as a double or triple lumen catheter). Ultrasound guidance should be used for central line placement whenever possible. An arterial line is highly recommended because it simplifies the often-required frequent laboratory assessments and allows close monitoring of blood pressure.

Transfusion Threshold
The generally accepted definition of postpartum hemorrhage is blood loss greater than 500 mL for vaginal delivery and 1000 mL for cesarean delivery.1 However, anesthesiologists, obstetricians, and nurses are often poor at visual estimation of blood loss. When providers are asked www.clinicalobgyn.com

198

Fuller and Bucklin A helpful tool to assess patients with the potential for inadequate perfusion due to hypovolemia is the American College of Surgeons classification of hypovolemic shock6 (Table 1). Although it is used to describe trauma patients who do not benefit from the increased blood volume and other physiologic changes of pregnancy, the basic principles are the same. In the early stages of blood loss, hypoperfusion causes an increase in circulating catecholamines, resulting in tachycardia and often normal to low-normal blood pressure. Later, the heart rate continues to increase in an effort to increase oxygen delivery to the tissues, pulse pressure decreases, and hypotension (often profound) is seen. These patients are frequently anxious, lethargic, and have pale mucous membranes. Patients in this clinical situation (stage III or IV hypovolemic shock) have lost 30% or more of their blood volume and almost always require blood transfusion.6 Even young, healthy parturients can have detrimental effects from severe anemia. In a study of intensive care unit

to quantify blood loss in simulated vaginal or operative deliveries, the results are inaccurate, especially at higher volumes, and there is little difference between the types of providers and level of experience.4 In 1 study that examined the utility of calibrated conical drapes for estimating blood loss at vaginal delivery, providers underestimated blood loss by up to 41% when presented with a simulated 2000 mL volume.4 On the other hand, at smaller volumes that would be seen when a patient has an intermittently bleeding placenta previa, providers may overestimate blood loss.5 So how does a clinician determine when a patient requires a transfusion? One must carefully assess the clinical situation, including noticeable bleeding and the potential for concealed blood (such as under surgical drapes or into the abdominal cavity). The patients vital signs, cognition, and coexisting diseases must also be considered. In this situation, there is no substitute for looking at the patient and assessing her vital signs, mental status, and urine output.
TABLE 1.
Estimated Blood Loss (mL) 0-750

Signs and Symptoms of Hypovolemic Shock6

Percent Blood Volume Lost (%) 10-15

Physiologic Changes

Heart Rate

Blood Pressure NC

Urine Output NC

Mental Status NC or mildly anxious

Likelihood of Transfusion Transfusion usually not necessary

750-1500

15-25

1500-2500

25-40

NC or mildly m circulating elevated catecholamines and fluid shifts usually compensate for blood loss m circulating <100 bpm catecholamines, peripheral vasoconstriction 100-120 bpm Hypoperfusion, moderate shock Extreme hypoperfusion; severe shock >120-140 bpm

NC or k pulse pressure

Slight k (20-30 mL/h) k (5-15 mL/h)

Anxiety, fright, or hostility

Transfusion possible

SBP 80-100 mm Hg; k pulse pressure

Anxiety, confusion

>2000

>40

kk Possibly SBP <80 mm Hg, complete may be anuria undetectable via noninvasive blood pressure cuff

Lethargy, loss of consciousness frequently observed

Transfusion almost always necessary Massive transfusion possible

bpm indicates beats per minute; NC, no change; SBP, systolic blood pressure.

www.clinicalobgyn.com

Blood Product Replacement (ICU) patients admitted with postpartum hemorrhage and hypovolemic shock, approximately 50% had evidence of myocardial ischemia as measured by elevated troponin levels. A significant risk factor in this population was hemoglobin (Hgb) of 6.0 g/dL or lower, especially when combined with systolic blood pressure less than 88 mm Hg, diastolic blood pressure of less than 50 mm Hg, and heart rate greater than 115 beats per minute.7 When hypoperfusion of this magnitude exists, the circulating oxygen carrying capacity needs to be increased. This is accomplished with packed RBCs (PRBCs). In published clinical guidelines, the ASA Task Force on Blood Product Replacement states that PRBC transfusion is rarely indicated with an Hgb level greater than 10 g/dL and virtually always indicated when Hgb levels fall below 6 g/dL.8 The decision to transfuse blood is based more on the physical examination including vital signs, coexisting diseases, and the potential for ongoing blood loss than on any laboratory value but it seems prudent to use an Hgb of 7 to 8 g/dL as a trigger for transfusion.1,9

199

Platelets
Platelets are prepared either by aphoresis from a single donor or by pooling 4 to 6 random donor platelet concentrates.11 An aphoresis unit of platelets should increase the platelet count by 25,000 to 30,000.12 Platelet transfusion is rarely indicated when the platelet count is greater than 100,000 cells/mm3, but should be considered before surgical procedures or in the presence of excessive bleeding with platelet counts less than 50,000 cells/mm3.8,11 Transfusion of ABO-incompatible platelets may decrease the lifespan of the platelets as well as increase the recipients overall production of anti-A, anti-B, and other alloantibodies.11 In the obstetric population, every effort should be made to avoid transfusing Rh positive platelets to an Rh negative recipient. If this occurs, Rh immune globulin should be given to prevent Rh sensitization and complications with future pregnancies.13

Clotting Factors
Fresh frozen plasma (FFP) contains all plasma clotting factors and proteins. It is collected from whole blood or plasma apheresis. FFP must be thawed before administration because it is stored at 181C to 301C, which can be problematic in an emergency. In the obstetric setting, FFP is used to treat microvascular bleeding due to coagulopathy or clotting factor deficiency in the presence of DIC or massive transfusion. The ASA Task Force on blood component therapy recommends FFP administration when the prothrombin time/international normalized ratio exceeds 2 times normal and/or the activated partial thromboplastin time is greater than 1.5 times the normal.8 Although these recommendations guide current therapy, recent literature suggests that clinicians should be more liberal with FFP administration, especially in the setting of massive transfusion. Trauma studies from the wars in Afghanistan www.clinicalobgyn.com

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a condition that results in hemorrhage and microvascular thrombosis. It occurs when an inciting event initiates the biodegradation of fibrinogen and clotting factors. The exact incidence of DIC in obstetrics is unknown but it is associated with many obstetric conditions, including amniotic fluid embolism (AFE), chorioamnionitis, placental abruption, retained products of conception, and preeclampsia.10 The association of DIC with obstetric hemorrhage necessitates assessment of coagulation with timely administration of clotting factors and platelets.

200

Fuller and Bucklin Errors may occur in many different steps in the transfusion process, including specimen labeling, patient misidentification, and laboratory errors. They seem to be more common during off hours.15 Frequently, more than 1 error occurs, but the most common error is failure to perform the final blood check before administration.15 In a simulated operating room environment, distraction of the anesthesiologist during blood administration led to omission of the standard blood check before the start of a transfusion.16 Clearly this has implications in the setting of an obstetric hemorrhage as the emergent clinical situation is fraught with the need to multitask and the probability of distraction is high. Often, the staff is working at off-hours and may not be familiar with each other or the labor ward. Extreme vigilance on the part of all staff involved in the blood administration process is paramount to protect patients from the possibility of human error causing harm. Hemolytic Reactions If erroneous blood product administration occurs, the most problematic complication is an acute hemolytic reaction, in which the recipients circulating antibodies destroy the transfused RBC. Signs and symptoms include fever, urticaria, nausea, chest and flank pain, hyperkalemia, hypotension, DIC, hemoglobinemia, and acute renal failure.17 Treatment for an acute hemolytic reaction is to stop the transfusion immediately and begin supportive care, such as blood pressure support with vasopressors if necessary, aggressive intravenous fluid replacement, diuresis, and alkalinization of the urine.17 Urine and plasma Hgb, an antibody screen, coagulation parameters, and a complete blood count should be sent to the laboratory. Donor blood and a sample of the patients blood should be sent to the blood bank to confirm incompatibility if an acute hemolytic reaction is suspected.17

and Iraq have consistently found increased survival rates in patients given larger amounts of FFP than laboratory data would suggest (ie, RBC to FFP ratio close to 1:1).14 It is unclear if this finding can be extrapolated to the obstetric population. However, as obstetric hemorrhage carries a high risk of coagulopathy it seems prudent to treat based on clinical signs and request FFP to be thawed early or include it as part of a massive transfusion protocol rather than wait for specific laboratory results.12 ABO compatibility should be considered whenever possible because anti-ABO antibodies are present in plasma.2 For example, type O plasma contains anti-A and anti-B antibodies and should not be given to a patient with type AB blood.2 Cryoprecipitate has large doses of Factor VIII and fibrinogen and is derived from FFP. When fibrinogen levels are below 80 to 100 mg/dL, typically in the presence of DIC or massive transfusion, cryoprecipitate can be helpful to treat microvascular bleeding.8,12 ABO compatibility is not as much of a concern as with other blood products because the amount of plasma transfused is minimal.2 For reference, all blood product components and their properties are listed in Table 2.
COMPLICATIONS ASSOCIATED WITH BLOOD PRODUCT ADMINISTRATION

Human Error The most common serious risk of blood transfusion is administration of blood to the wrong recipient as a result of human error.15 According to the Serious Hazards of Transfusion (SHOT) hemovigilance system in the United Kingdom (UK), 60% of transfusion-related adverse events were due to the incorrect blood component being transfused. According to the SHOT data from 1996 to 2003, the risk of an ABO-incompatible transfusion is 1:100,000, with the risk of death from the incompatible transfusion 1:1,500,000.15 www.clinicalobgyn.com

Blood Product Replacement

TABLE 2.
Product Packed red blood cells

201

Blood Product Components1,9,11

Contents Red blood cells Recommendations for Transfusion Improve oxygen carrying capacity Almost always for Hgb <6 g/dL Rarely for Hgb >10 g/dL Microvascular bleeding with platelet counts <50,000 cells/mm3 Notes Compatibility Information Type-specific and crossmatched blood preferred Type O, Rh can be used in emergency

Platelets

Platelets

Fresh frozen plasma

All plasma proteins and clotting factors

Cryoprecipitate

Factor VIII and fibrinogen

Microvascular bleeding due to clotting factor deficiency INR >2 normal aPTT >1.5 normal If massive transfusion is expected, consider RBC:FFP ratio close to 1:1 Microvascular bleeding due to fibrinogen deficiency Fibrinogen <80-100 mg/dL

Derived from pooled donors or aphoresis Blood product most often associated with bacterial contamination Must be thawed before administration (20-30 min) Blood product most often associated with TRALI

ABO compatibility preferred ABO-incompatible platelets can be given but may have k lifespan and m risk of alloimmunization Rh compatibility necessary ABO compatibility preferred

ABO compatibility not necessary

aPTT indicates activated partial thromboplastin time; FFP, fresh frozen plasma; Hgb, hemoglobin; INR, international normalized ratio; RBC, red blood cell; TRALI, transfusion-related acute lung injury.

Previous transfusions and pregnancies can lead to antibodies at levels too low to be detected during crossmatch. A delayed hemolytic reaction can result from extravascular hemolysis of donor RBC and is usually seen approximately 1 week after an apparently uneventful transfusion. The signs and symptoms can be very serious but are usually self-limited and include anemia, mild fever, increased unconjugated bilirubin, jaundice, hemoglo-

binuria, decreased haptoglobin, and spherocytosis on the blood smear.17 Transfusion-transmitted Infection The safety of banked blood has improved dramatically since the development of viral nucleic acid testing.18 The incidence of transfusion-transmitted infection is now so low that mathematical models are used to estimate the probability of pathogen transmission. The current incidence of www.clinicalobgyn.com

202

Fuller and Bucklin

ALTERNATIVES TO BANKED BLOOD

various transfusion-transmitted infectious disease is summarized in Table 3.18 Although the low incidence of transmission is very encouraging, the blood supply must be constantly surveyed because the genetic diversity of viruses such as HIV is increasing and other potential pathogens constantly surface. West Nile virus has been a pathogen of concern since it entered the United States in 1999 and was first reported to be transmittable by transfusion in 2002. Nucleic acid testing for West Nile virus was promptly developed and is routinely used, especially in areas of high prevalence.18 Variant Creutzfeldt-Jakob disease, has proven to be associated with transfusion. It is transmitted by a prion protein and therefore not detectable by nucleic acid testing. To date, 4 cases, all in the UK, have been attributed to infected donors and transmitted by transfusion.18 In France and the UK, where variant Creutzfeldt-Jakob disease transmission is a significant concern, specific steps to reduce transmission have been taken such as importing plasma, leukoreduction, and using single donor (as opposed to pooled) platelets.18 Despite the ongoing threat of new transfusion-transmitted pathogens, the most common cause of fatal acute transfusion-associated infection is a bacterial infection from contaminated blood products.9,11,19 Patients presentations range from mild fever to septic shock. All blood products have the potential for bacterial contamination, but platelets are stored at room temperature and more likely to support bacterial growth. The incidence of bacterial contamination of platelets is estimated to be 1:2000 units with approximately 16% to 25% of these associated with sepsis.19 The most common pathogen is Staphylococcus aureus.9 Clinical suspicion should be raised in any patient who develops a fever within 6 hours after platelet transfusion and antibiotic therapy should be considered.9 www.clinicalobgyn.com

Autologous Blood Donation For patients at risk for hemorrhage who may be difficult to crossmatch, autologous blood donation may be a reasonable alternative to banked blood. Advantages of this technique are immediate blood availability when the patient presents emergently as well as fewer risks of immune modulation, bacterial contamination, or hemolytic reactions. A published protocol for autologous blood donation during pregnancy exists, in which 82 patients with placenta previa began donation at 32 weeks gestation. Each week, 400 mL of blood was removed with a total volume of 1200 to 1500 mL stored. Fetal heart rate monitoring was performed with each donation and no abnormalities were observed.21 The patients who donated autologous blood had a significantly lower requirement for homologous blood. However, 71% of those who donated autologous blood received a blood transfusion compared
TABLE 3. Estimated Risks of Blood Transfusion15,1720
Viruses HIV Hepatitis B Hepatitis C 1:1.4 million-1:2 million 1:60,000-1:200,000 1:800,000-1:1.6 million

Bacteria Contamination 1:2000 Sepsis 1:12,000 Parasites Malaria Rare, less than 1/y Prions Rare Variant CreutzfeldtFour reported cases Jakob disease Other Transfusion-related complications Transfusion error 1:14,000-1:19,000 Acute hemolytic reaction 1:250,000-1:1 million Delayed hemolytic 1:1000 reaction TRALI 1 5000
HIV indicates human immunodeficiency virus; TRALI, transfusion-related acute lung injury.

Blood Product Replacement with 12% who did not predonate.21 Although it may be tempting to readminister blood the patient has already donated, it is important to understand that the most significant risk to the patient has not been removed, namely human error. In fact, the incidence of error resulting in ABO mismatch is similar for both autologous and homologous blood.20 Intraoperative Cell Salvage The use of an intraoperative cell salvage device, or cell saver, is becoming more common in obstetrics. When using this technique, blood is suctioned from the operative field into a special canister. This is followed by cell washing, suspension in saline, and reinfusion to the patient.22 Cell salvage is controversial due to the concern that the blood may be contaminated with amniotic fluid when reinfused to the patient and incite the syndrome associated with AFE.22 AFE is associated with coagulopathy and cardiovascular collapse, the cause of which is unknown. Tissue factor, fetal squamous cells, and meconium are all potentially present in amniotic fluid and may be involved in the pathogenesis of AFE. Cell salvage systems effectively remove activated tissue factor from amniotic fluid-contaminated blood.22 The addition of a leukocyte depletion filter significantly increases the safety as it reduces the concentration of fetal squamous cells and the risk of bacterial contamination.22 In addition to these in vitro demonstrations of cell salvage technologys efficacy in reducing amniotic fluid contamination, reports on its clinical use for relatively large series of obstetric patients are surfacing. In a multicenter historical cohort study, 139 patients received autologous blood transfusion during cesarean delivery via intraoperative cell salvage technique with no patients experiencing AFE or adult respiratory distress syndrome.23

203

Another recent publication reports incorporating cell saver for all patients undergoing cesarean delivery who were at risk for hemorrhage. The technology was used for 46 patients, with 19 receiving a median volume of 390 mL and without adverse events.24 Although these reports are encouraging regarding the safety of cell salvage, it is still possible that AFE is so rare that the numbers reported are not large enough to capture the event. One case report exists where a patient with multiple coexisting diseases, including HELLP syndrome, experienced hypoxia, cardiovascular collapse, and death within minutes of receiving cell-salvaged blood during cesarean delivery.25 A leukocyte depletion filter was not used. Although the patient had other diseases making the exact cause of death unclear, a clinical diagnosis of AFE was made. Fetal hemoglobin is present in variable amounts in cell-salvaged blood.22 This raises the potential for alloimmunization in an Rh negative mother. Therefore, any Rh negative obstetric patient who receives processed cell-salvaged blood during cesarean delivery should receive anti-D immune globulin. A Kleihauer-Betke test should be considered to determine the exact dosage of anti-D immune globulin necessary due to the variable fetal hemoglobin concentration in the cell-salvaged blood.22 As obstetric hemorrhage often occurs rapidly and at unpredictable times, a significant deterrent to the clinical use of intraoperative cell salvage is the availability of personnel who know how to operate the equipment. One solution to this problem is to train all labor and delivery personnel to use the cell salvage device.24 Despite potential drawbacks, there is a growing body of evidence to support the safety of cell salvage. It is a useful alternative to banked blood and its use should be considered in patients at high risk for hemorrhage who would be otherwise www.clinicalobgyn.com

204

Fuller and Bucklin core hypothermia. Treatment of hemorrhage with RBC transfusion worsens the coagulopathy by diluting platelets and clotting factors and can exacerbate hypothermia and acidosis.26 In fact, recent trauma literature supports early use of FFP in an effort to attenuate this cycle of events.14 Although timely administration of platelets and clotting factors is imperative, one cannot forget the importance of maintaining temperature in these patients. Hypothermia can result from exposure of internal organs during surgery, vasodilation and redistribution during anesthesia, and the blood transfusion itself. Blood is stored at 11C to 61C, which places patients requiring several units at particular risk. Extreme hypothermia has many undesirable effects, including coagulopathy, decreased tissue perfusion, arrhythmias, and impaired drug activity and metabolism.26 Core temperature monitoring (usually via an esophageal temperature probe) is essential whenever transfusion is administered. Every effort should be made to maintain normothermia, including the use of a forced air warming device, fluid warmer, and warming the operating room. Plasma calcium levels should be measured during massive transfusion because the citrate from the preservative in the blood product can bind plasma calcium. Hypocalcemia can cause hypotension, tetany, and cardiac arrhythmias and should be treated with intravenous calcium chloride.17 In addition, potassium can diffuse out of RBCs during storage, leading to hyperkalemia in patients requiring transfusion. Usually the excess potassium is moved into the cells via active transport or excreted in the urine, but this may not occur in critically ill patients or those with renal impairment. Potassium levels should be monitored and the patient should be treated for hyperkalemia, especially if electrocardiogram changes such as peaked T waves and wide PR and QRS interval develop.17

difficult to crossmatch or object to blood transfusion. Massive Transfusion Massive transfusion is defined as administration of greater than 10 units of PRBC.14 The need for large amounts of blood can occur very quickly in obstetrics. Even the most expedited laboratory testing (ie STAT) can take up to 60 minutes for results, so waiting for laboratory evidence can result in a delay of treatment. In these cases, time is of the essence and the response must be coordinated. A massive transfusion protocol can be very helpful and is highly recommended.3,12,14 The ideal protocol is formed in conjunction with transfusion services and should include the provision for timely administration of clotting factors. One such protocol for use in obstetrics is published and includes the delivery of 6 units of PRBC, 4 units of FFP, and 1 aphoresis unit of platelets upon activation.12 It is imperative that all parties involved with transfusion (nurses, anesthesiologists, obstetricians, desk clerks, blood bank personnel) be aware of the protocol and its implementation. Practical aspects, including how to acquire and deliver laboratory specimens and transport blood to the obstetric suite should be discussed and posted in an easily accessible location before an emergency. Clinical drills for obstetric hemorrhage scenarios for all personnel can also be helpful.1,3 Most massive transfusion protocols recommend early administration of clotting factors in an effort to avoid the bloody vicious cycle of acidosis, hypothermia, and coagulopathy.12,14 This lethal triad has been studied most in trauma patients and the incidence in obstetric patients is unknown, but all patients requiring massive transfusion are at risk. During a hemorrhage severe enough to require massive transfusion, active hemorrhage is exacerbated by the coagulopathy that is associated with metabolic acidosis and www.clinicalobgyn.com

Blood Product Replacement Transfusion-associated Acute Lung Injury Transfusion-associated acute lung injury (TRALI) is an acute respiratory distress syndrome, which can present during or up to 6 hours after transfusion.27,28 According to the United States Food and Drug Administration, in 2006 TRALI was responsible for 50% of transfusionrelated deaths, making it the leading cause of death from transfusion.17,27 It is characterized by noncardiogenic pulmonary edema manifesting as hypoxia, fever, hypotension, and bilateral infiltrates on chest radiograph.17,27 TRALI is thought to occur in approximately 1 out of 5000 transfusions of blood or blood products but the true incidence is unknown because it is difficult to differentiate from other causes of acute lung injury.27 One case report of TRALI in the obstetric population exists. A patient received blood products (FFP and PRBCs) while undergoing surgery for a ruptured ectopic pregnancy. She quickly developed pulmonary edema, hypoxia, hypotension, and tachycardia. The transfused blood was subsequently found to contain human leukocyte antigen (HLA) antibodies to one of the patients antigens.29 This case is consistent with the leading hypothesis for the pathogenesis of TRALI.30 A donor HLA or granulocytespecific antibody is transfused into a recipient who possesses the corresponding leukocyte antigens.30 The antibody-antigen interaction initiates a cascade of cellular activity in the lung resulting in endothelial damage and capillary leakage into alveoli.30 It has been postulated that a preexisting clinical condition in the patient such as surgery, trauma, sepsis, or massive transfusion causes activation of the pulmonary endothelium and makes it more prone to endothelial damage.30 Among the blood components, transfusion with FFP carries the highest risk of TRALI.17 Multigestational women and people with a history of prior transfusions

205

are the most likely donors to be implicated in cases of TRALI.17 Transfusion-related Immunomodulation The effect that RBC transfusion has on the immune system is an area of active investigation. There is an increased incidence of postoperative infection in surgical patients who have received RBC transfusion, which seems to be higher in patients presenting with trauma and/or requiring emergency surgery.9,17,31 The cause of the increased infection rate is unknown but autologous blood does not seem to confer the same risk.9,17,31 In ICU patients, RBC transfusion seems to be associated with increased mortality, longer ICU stays, and longer hospital stays.9,17,31 The mechanism of transfusion-related immunomodulation is unclear. Theories include that immunosuppression is caused by one or a combination of the following: immunologically active allogenic white blood cells (WBCs), soluble WBC mediators in the RBC supernatant, or soluble HLA peptides in the allogenic plasma.31 Although trials are not conclusive, it is possible that the leukoreduction of WBC can decrease some of the immunomodulatory effects of transfusion.31 This will be an active area of investigation in the future and very little is known about immunomodulatory effects in obstetric patients. However, the current state of knowledge suggests that RBC transfusion must be viewed as a complex immunomodulatory event, which may carry the potential for adverse outcomes. Activated Recombinant Factor VII One of the most exciting advances in transfusion medicine has been the incorporation of activated recombinant factor VII (rFVIIa) for treatment of intractable coagulopathy associated with hemorrhage (Table 4). Identical in structure and function to human factor VIIa, rFVIIa was developed to prevent or control www.clinicalobgyn.com

206

Fuller and Bucklin

Use of Activated Recombinant Factor VII in Obstetrics3236
Mechanism of Action Binds tissue factor at site of injury Activates Factors X -Xa; IX-IXa Response Time Usually within 20-30 min If no response, consider repeating dose Potential Complications Thrombosis, including CVA, MI, DVT/PE Rare in obstetric population

TABLE 4.

Indication Treatment of coagulopathy associated with massive hemorrhage Originally developed to treat bleeding in hemophilia patients with factor inhibitors

Dose 50100 mcg/ kg IV May be repeated once

Notes Requires circulating clotting factors as substrates Works best in the presence of normothermia

CVA indicates cerebrovascular accident; DVT, deep venous thrombosis; MI, myocardial infarction; PE, pulmonary embolism.

bleeding in patients with hemophilia A or B with inhibitors to factors VIII and IX. It is now used in many different clinical situations and is effective for treatment of life-threatening obstetric hemorrhage. Several case reports, 1 nonrandomized trial, and multidisciplinary guidelines have been published to date regarding its use in obstetrics. rFVIIa acts by binding with tissue factor to augment the intrinsic clotting pathway by directly activating factors IX and X.32,33 The dose is 50 to 100 mcg/kg intravenously, with most patients responding to the drug within 30 minutes. It can be repeated every 2 hours until hemostasis is achieved, but most of the patients require only a single dose.1,32,34 Thrombotic events are the most commonly reported problems associated with factor VIIa administration and include cerebrovascular accidents, myocardial infarction, pulmonary embolism, and clotting of indwelling devices.35 In the only trial published with a comparison group, a total of 34 patients met the criteria for postpartum hemorrhage, with 18 patients receiving rFVIIa (based solely on drug availability) and 16 patients not receiving the drug.34 Patients who received rFVIIa had improved coagulation status, fewer RBC transfusions, and lower mortality. No adverse events www.clinicalobgyn.com

were reported.34 Eighty-three percent of patients responded to the first dose with another 5% responding to the second dose. Over 80% of the responders had improvement in their coagulopathy within 30 minutes of receiving the drug.34 The optimal timing of rFVIIa administration is unknown but reports suggest improved outcome when rFVIIa is administered relatively early in a hemorrhagic emergency.32 As rFVIIa uses circulating clotting factors as substrates, it is important to ensure adequate levels of platelets and clotting factors (by administration of blood products if necessary) before its administration.32 The activity of rFVIIa decreases in the presence of hypothermia and acidosis, highlighting the importance of its use before the patient developing some of the consequences of massive transfusion.32 Early administration may allow patients to preserve fertility by treating the coagulopathy before hysterectomy. All of these considerations must be balanced with the cost of the drug and the potential for the patient to respond to other measures. In light of this clinical quandary, guidelines were established by a multidisciplinary Australian group in which they suggest administration after 8 to 12 U PRBC, 4 to 8 U FFP, platelets, and cryoprecipitate but before hysterectomy.36

Blood Product Replacement

207

Conclusions
Blood product administration is a relatively common event. Timely administration of clotting factors may prove to be extremely beneficial in the obstetric population but studies are needed to determine if the data from trauma patients applies to obstetrics. Blood product administration can be lifesaving but it should never be viewed as innocuous. It should only be administered for specific clinical indications. Alternatives to banked blood should be considered if time and resources permit. rFVIIa has emerged as a useful adjuvant to blood products in the setting of massive hemorrhage.

References
1. ACOG Practice Bulletin: clinical management guidelines for obstetriciangynecologists number 76, October 2006: postpartum hemorrhage. Obstet Gynecol. 2006;108:10391047. 2. Yazer MH. The blood bank black box debunked: pretransfusion testing explained. Can Med Assoc J. 2006;174:2932. 3. Practice Guidelines for obstetric anesthesia: an updated report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Anesthesiology. 2007;106:121. 4. Toledo P, McCarthy RJ, Hewlett BJ, et al. The accuracy of blood loss estimation after simulated vaginal delivery. Anesth Analg. 2007;105:17361740. 5. Yoong W, Karavolos S, Damodaram M, et al. Observer accuracy and reproducability of visual estimation of blood loss in obstetrics: how accurate and consistent are health-care professionals? Arch Gynecol Obstet. 2009. [Epub ahead of print]. 6. Shock. American College of Surgeons Committee on Trauma: Advanced Trauma Life Support for Doctors. Chicago, IL: American College of Surgeons; 2004: 69102. 7. Karpati PC, Rossignol M, Pirot M, et al. High incidence of myocardial ischemia during postpartum hemorrhage. Anesthesiology. 2004;100:3036.

8. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006; 105:198208. 9. Goodnough LT, Brecher ME, Kanter MH, et al. Transfusion Medicine: first of two parts. N Engl J Med. 1999;340: 438447. 10. Bick RL. Disseminated intravascular coagulation: A review of etiology, pathophysiology, diagnosis, and management: Guidelines for care. Clin Appl Thromb Hemost. 2002;8:131. 11. Slichter SJ. Evidence-based platelet transfusion guidelines. Am Soc Hematol Educ Prog. 2007;1:172178. 12. Burtelow M, Riley E, Druzin M, et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion. 2007;47: 15641572. 13. Ayache S, Herman JH. Prevention of D sensitization after mismatched transfusion of blood components: toward optimal use of RhIG. Transfusion. 2008;48: 19901999. 14. Shaz BH, Dente CJ, Harris RS, et al. Transfusion management of trauma patients. Anesth Analg. 2009;108:17601768. 15. Stainsby D. Errors in transfusion medicine. Anesth Clin North Am. 2005;23: 253261. 16. Liu D, Grundgeiger T, Sanderson PM, et al. Interruptions and blood transfusion checks: lessons from the simulated operating room. Anesth Analg. 2009;108: 219222. 17. Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108:759769. 18. Allian J-P, Stramer SL, Carneiro-Proietti ABF, et al. Transfusion-transmitted infectious disease. Biologicals. 2009;37: 7177. 19. Goodnough LT. Risks of blood transfusion. Anesth Clin North Am. 2005;23: 241252. 20. Linden JV, Wagner K, Voytovich AE, et al. Transfusion errors in New York

www.clinicalobgyn.com

208

Fuller and Bucklin

State: an analysis of 10 years experience. Transfusion. 2000;40:12071213. Yamada T, Mori H, Ueki M. Autologous blood transfusion in patients with placenta previa. Acta Obstet Gynecol Scand. 2005;84:255259. Allam J, Cox M, Yentis SM. Cell salvage in obstetrics. Int J Obstet Anesth. 2008; 17:3745. Rebarber A, Lonser R, Jackson S, et al. The safety of intraoperative autologous blood collection and autotransfusion during cesarean section. Am J Obstet Gynecol. 1998;179:715720. King M, Wrench I, Galimberti A, et al. Introduction of cell salvage into a large obstetric unit: the first six months. Int J Obstet Anesth. 2009;18:111117. Oei SG, Wingen CBM, Kerkkamp HEM. Cell salvage: how safe in obstetrics? Int J Obstet Anesth. 2000;9:143. Eddy VA, Morris JA, Cullinane DC. Hypothermia, coagulopathy, and acidosis. Surg Clin North Am. 2000;80: 845854. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005; 33:721726. Moore SB. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis. Crit Care Med. 2006;34(suppl):S114S117. 29. Droog W, Thiel SWv, Sleeswijk SJ, et al. Complications due to transfusion-related acute lung injury. Obstet Gynecol. 2009; 113:560563. 30. Mair DC, Hirschler N, Eastlund T. Blood donor and component management strategies to prevent transfusion-related acute lung injury (TRALI). Crit Care Med. 2006;34(suppl.):S137S143. 31. Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev. 2007;21:327348. 32. Karalapillai D, Popham P. Recombinant factor VIIa in massive postpartum haemorrhage. Int J Obstet Anesth. 2007; 16:2934. 33. Hedner U, Erhardtsen E. Potential role for rFVIIa in transfusion medicine. Transfusion. 2002;42:114124. 34. Hossain N, Shamsi T, Haider S, et al. Use of recombinant activated factor VII for massive obstetric hemorrhage. Acta Obstet Gynecol Scand. 2007;86:12001206. 35. OConnell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. J Am Med Assoc. 2006;295: 293298. 36. Welsh A, McLintock C, Gatt S, et al. Guidelines for the use of recombinant activated factor VII in massive obstetric haemorrhage. Aust N Z J Obstet Gynaecol. 2008;48:1216.

21.

22. 23.

24.

25. 26.

27.

28.

www.clinicalobgyn.com