Massive Transfusions and Coagulopathy Christine Mai, MD Faculty Advisor: Mauricio Gonzalez, MD Boston University Medical Center Anesthesiology

Department 10/26/06 Hello. My name is Christine Mai, Im a second year resident in Anesthesiology. Today, I will be discussing the topic of massive transfusions and problems with coagulopathy arising from fluid resuscitation. In 1994, the American Society of Anesthesiologists established the Task Force on Blood Component Therapy to develop evidence-based guidelines for transfusing pRBC, FFP, platelets, and cryoprecipitate in perioperative and peripartum settings. More than 22 million blood components are transfused each year in the US mainly to surgical and obstetric patients. The benefits of transfusions include improved tissue oxygenation and decreased bleeding. However, transfusions are not without risks or costs. Transmission of infectious diseases (ie. Hepatitis, HIV, CMV), hemolytic and nonhemolytic transfusion reactions, immunosuppression, alloimmunization are among the many problems associated with transfusion. More importantly, in cases of trauma where massive transfusions are necessary, problems with coagulopathy often complicate perioperative and postoperative recovery. Massive transfusion is defined by the American Association of Blood Banks as the replacement of one blood volume (equivalent to 10 units of blood) in any 24 hour period, or half of the blood volume (five units of blood) in any 4 hour period. For the purpose of clinical estimation of volume of blood loss, hemorrhage is divided into four classes. Estimated blood loss, clinical signs of pulse rate, blood pressure, capillary refill time, respiratory rate, urine output and mental status are indicators for guiding fluid resuscitation therapy with crystalloids or blood. Fluid management is based on parameters such as maintenance, deficits, insensible loss, and estimated blood loss. Maintenance is determined by using calculated body weight and the 4:2:1 rule. Deficits include volumes such as NPO status, bowel prep, urine output, NG tube or chest tube drainages. Insensible loss is dependent on the type of surgery and the amount of body exposure. Estimated blood loss is replaced either by crystalloids in a 3:1 ratio or by colloids via a 1:1 ratio. The allowable blood loss equation is a formula that aids in determining when transfusion of blood products should be initiated, particularly in elective surgical cases. This equation is based on estimated blood volumes which are approximately 75 cc/kg in adults, 80 cc/kg in children, and 85 cc/kg in neonates. Fluid resuscitation often begins with crystalloids, particularly normal saline, lactated ringer, or plasmalyte. It is important to review the electrolyte components, pH, and

osmolality of each of these crystalloids, because certain fluids are indicated and contraindicated in certain situations. Now we will discuss about the screening tests for ordering blood products. There are two types of screening tests: a type and screen test and a type and crossmatch (ie. Compatibility test). Type and screen refers to determination of ABO-Rh and the presence of the most commonly found unexpected antibodies. This is performed by incubating the recipients serum with selected reagent RBCs (ie. screen cells) that contain all antigens capable of inducing clinically significant RBC antibody reactions. In addition, the presence or absence of Rh (D) antigens are tested. Individuals who do not have the Rh antigens are known as Rh negative, and develop antibodies against Rh antigens once exposed to it via a transfusion or a pregnancy with an Rh positive fetus. ABO incompatibility is the most tragic and severe reaction, often due to accidental transfusion of ABO-incompatible blood. These reactions occur when native antibodies (anti-A or anti-B) in the recipient react to the A or B antigens in the donors blood, resulting in rapid intravenous hemolysis. Type and screen tests are mainly ordered during elective cases when the probability of blood loss and transfusion are high. If blood is needed for emergent transfusion, a crossmatch can be performed on the type and screen sample to reconfirm ABO-Rh typing. A type and crossmatching test includes an ABO-Rh type (such as in T&S), crossmatch, and antibody screening. Crossmatching is essentially a trial transfusion within a test tube between donor RBCs with recipient serum to detect a potential for serious transfusion reaction. The purpose of crossmatching is to re-check ABO-Rh typing, detect antibodies that are incomplete or do not agglutinate easily, and detect antibodies in other blood group systems (ie. Rh, Kell, Kidd, Duffy blood groups). The antibody screen is a trial transfusion between the recipients serum and commercially supplied RBCs with antigens that will react with antibodies commonly implicated in non-ABO hemolytic transfusion reactions. This test is also performed on the donors serum to screen for unexpected antibodies to prevent their introduction to the recipients serum. This test is otherwise known as the Coombs test. Blood product transfusion consists of packed red blood cells, fresh frozen plasma, platelets and cryoprecitate. Approx. 12 000 000 units of RBC are transfused yearly in the US. Packed red cells are indicated for patients needing red cells for oxygen carrying capacity rather than for volume replacement (ie. CHF patients). In surgical situations when volume expansion is needed, plasma and platelet products should also be transfused simultaneously with pRBC to avoid hemodilution coagulopathy. Packed red cells contain the same amount of hemoglobin as whole blood, except that much of the plasma has been removed. The hemocrit in pRBC is 70% compared to 40% in whole blood. Each unit of pRBC contains 250-350 cc, which increases Hct 3-4% or hemoglobin 1g/dL. Large amount of transfusions should be warmed to 37 degrees C. Packed red cells should be diluted with either normal saline or plasmalyte when given in massive transfusions. Avoid Lactated Ringers because the citrate preservative in pRBC chealates with calcium in the LR.

A common adverse event that occurs with massive transfusion is citrate toxicity. Citrate toxicity is not caused by the citrate in the blood product but rather the calcium binding to the citrate preservative in transfused blood leads to hypocalcemia. Signs of citrate intoxication include hypocalcemia, hypotension, narrowed pulse pressure, and increased intraventricular end-diastolic pressure and central venous pressure. Cardiovascular depression can occur if transfusion rate exceeds 1 unit of blood per 5 mins. Risk factors for citrate intoxication include hypothermia, liver disease, and liver transplantation. Ionized calcium should be monitored during massive transfusion, and repleted with Calcium Chloride when necessary. Blood usually coagulates appropriately when coagulation factors are at least 20-30% normal and when fibrinogen levels are greater than 75mg/dL. During massive transfusion when a whole volume of blood is given, the concentration of coagulation factors will be one-third of the original concentration. Therefore, it is important to be aware of the amount of pRBC given and check coagulation studies (INR/PTT) frequently in anticipation of early administration of FFP. Fresh frozen plasma contains all the plasma proteins, including factors V and VIII. Indications for FFP include: 1) urgent reversal of warfarin therapy 2) correction of isolated coagulopathy factor deficiencies (documented by lab finding) 3) correction of microvascular bleeding in the presence of increased (>1.5 x normal) prothrombin time or partial thromboplastin time 4) correction of microvascular bleeding due to coagulation factor deficiency in patients transfused with > one blood volume and when PT and pTT can not be obtained in a timely fashion 5) Antithrombin III deficiency 6) Treatment of immunodeficiencies 7) Treatment of thrombotic thrombocytopenia purpura FFP increases level of each clotting factor by 2-3%. FFP needs to be ABO-compatible but does not require crossmatching Rh typing. Platelets transfusion are indicated for massive transfusion thrombocytopenia < 50 x 109/L, or if there is known platelet dysfunction and microvascular bleeding. Platelets are pooled from donored blood (ie. 5 donors=5000 plt/microL). Each 10-12 units of pRBC decrease platelet count by 50%. For replacement therapy, 5-10 units of plt (ie. 5000 10 000 plt/microL) should be given when 10-20 units of pRBC has been transfused. Platelets must be transfused slowly to avoid hypotensive reaction. Cryoprecipitate is collected by thawing FFP at 4 degrees C. It contains von Willebrand factor, factor VIII, XIII, fibrinogen, and fibronectin. Indications for cryoprecipitate include: patients with von Willebrands disease unresponsive to Desmopressin, bleeding patients with vWD, patients with congenital fibrinogen deficiency, bleeding patients with fibrinogen levels < 80-100mg/dL, and hemophilia A. One unit of cryoprecipitate will

increase fibrinogen concentration by 50mg/dL. Cryoprecipitate should be administered rapidly through a filter (ie. 200 cc/hr), and infusion should be completed within 6 hrs of thawing. Pathophysiology of coagulopathy results from hemodilution, hypothermia, unfractionated blood products, and DIC 1) Hemodilution: -Crystalloid -Colloid 2) Hypothermia (<35 degrees C): slows the activity of the coagulation cascade, reduces the synthesis of coagulation factors, increase fibrinolysis, decrease platelets and affects platelet function. Pts who are hypothermic and acidotic develop clinically significant bleeding despite adequate blood, plasma and platelet replacement. 3) Blood Components: - Red Blood Cells-contribute to thrombosis and hemostasis. Packed red cells contain ADP that activates platelets, activate platelet cyclooxygenase, increase generation of thromboxane A2, thereby increasing thrombin. -Abnormalities of Prothrombin time (PT) and activated partial thromboplastin time (aPTT) occur after transfusion of 12 units of pRBC -Coagulation Factors-Blood loss greater than EBVx2 resulted in deficiency of prothrombin, factor V, factor VII, and platelets -Platelet- Thrombocytopenia occur after transfusion of 20 units of pRBC 4) DIC: An acquired syndrome secondary to systemic and excessive activation of coagulation. -In trauma patients, tissue trauma, brain injury, shock, tissue anoxia, hypothermia contributes to DIC and microvascular bleeding. -Diagnosis: D-dimer>500mcg/L, increased INR, thrombocytopenia, microvascular bleeding +/- thrombosis -Risk factors: acidosis, hypothermia, hypotension, increase in injury severity The Transfusion Protocol from Parkland Memorial Hospital in Dallas, Texas is a cooperative effort between the Pathology, Anesthesiology and Trauma Surgery departments with the goal to support rapid transfusion in the ER and OR with regular shipments of blood products released automatically on a timed basis. The design for massive transfusion protocol is based on patterns of coagulopathy that may develop during trauma care. Shipments of 5 units pRBC, 2 units FFP are dispensed q30mins. Platelets (5 pooled units) are added every other shipment. Cryoprecipitate (10 pooled units) are added every third shipment. Human recombinant Factor VIIa is added during the third shipment (sent with pRBC units 11-15). rFVIIa is used early during transfusion because of the rapid decline of Factor VII during trauma blood loss. Thus far, the patient survival rate to date with the protocol is approx. 50%. Anesthesiologists and trauma surgeons at Parkland believe that the protocol provides blood products more efficiently, and that more FFP, platelets and cryoprecipitate are given. Nevertheless, further studies are needed to see the effects of the protocol in incidences of coagulopathy in the long term.

Recombinant coagulation factor VIIa (rFVIIa) (Novoseven), is a Vitamin K-dependent glycoprotein recently licensed by the FDA for treatment of bleeding in individuals with hemophilia A and B inhibitors, acquired inhibitors (e.g. anti-VIII), and congenital factor VII deficiency. The site of action of rFVIIa is the extrinsic coagulation cascade. It promotes the activation of factor X to Xa and factor II (prothrombin) to IIa (thrombin); thereby, bypassing the intrinsic pathway (factors VIII and IX). This is potentially beneficial in patients with acquired inhibitors to factor VIII or IX, who no longer respond to factor VIII or IX concentrates, and patients with congenital factor VII deficiency. FVIIa promotes clot formation and hemostasis at the site of injury with no evidence of activation of the coagulation system, e.g. decreased in platelets, fibrin split products, or fibrin monomer. The major effect of rFVIIa is to shorten the prothrombin time (PT). The extent of PT shortening, however, does not correlate with clinical efficacy of rFVIIa. Therefore, patients treated with rFVIIa should be monitored for blood loss, transfusion requirement, and hemoglobin. Several studies have shown the efficacy of rFVIIa as an adjuvant therapy in managing hemorrhage due to trauma. Among blunt trauma patients, rFVIIa reduced the need for massive blood transfusions. There is no increased risk for adverse reactions such as thromboembolic events, and it avoids the risk associated with plasma such as bloodborne viral transmission. There has been no evidence of allergic reaction or activation of coagulation, thrombocytopenia, or disseminated intravascular coagulation. In addition, complications associated with microthrombus generations such as multi-organ failure and ARDS tend to be less frequent with rFVIIa. A drawback to rFVIIa is the short half-life, 2-3 hrs, which requires frequent dosing and results in high cost. Although continous infusion is an option, it is not recommended at this point because local thrombophlebitis is a major complication, possibly related to the high concentration of rVIIa in peripheral veins. The initial recommended dose of rFVIIa is 90 mg/kg, continued every 2-3 hours. Once bleeding and hemoglobin have stabilized, taper to every 6-8 hours, then every 12-24 hours, and then stop. Although there are no algorithms for the management of coagulopathy in massive transfusion, some key take home pointers from this lecture are: -Maintaining core body temp > 35 degrees C is a first-line, effective strategy to improve hemostasis during massive transfusion. -Correct Acidosis by re-establishing adequate tissue perfusion and oxygenation. -Check labs frequently (ie. ABGs, lytes, coags, plt, fibrinogen, lactate). -Replete electrolytes as necessary, particularly calcium. -Consider early administration of FFP and platelets during massive transfusion with pRBC. Stay ahead of the game to prevent coagulopathy in the first instance.

References: 1. ASA Practice Guidelines For Blood Component Therapy 2. Mattox, K. Hemorrhage Complications of Trauma. 1994: 1-12 3. Forestner, J. Massive transfusion protocol for trauma ASA Newsletter. Nov. 2005. Vol. 69 4. Miller, R. Transfusion Therapy Millers Anesthesia. 6th ed. 2005: 1799-1827 5. Ketchum, L, Hess, J, Hiippala, S. Indications for early fresh frozen plasma, cryoprecipitate, and platelet transfusion in trauma. The Journal of Trauma. 2006; 60(6): S51-S58. 6. Hardy, JF, de Moerloose, P, Samama, M. Massive transfusion and coagulopathy: pathophysiology and implications for clinical management Canadian Journal of Anesthsiology. 2004; 51(4): 293-310 7. Ragni, M. Recombinant Factor VIIa: a new product for factor VIII and IX inhibitor Transfusion medicine update: The Institute of Transfusion Medicine. Nov/Dec. 1999 8. Loudon, B, Smith, MP. Recombinant factor VIIa as an adjunctive therapy for patients requiring large volume transfusion: a pharmacoeconomic evaluation Internal Medicine Journal. 2005; 35: 463-467