Transfusion and Coagulation Therapy

Historical Aspects of Transfusion

The observation by Harvey in 1628 that blood circulates in a closed vascular system was pivotal in the practice of blood transfusion. As blood was recognized as vital to sustain life, Denis in Paris and Lower in Oxford attempted xeno-transfusion (animal blood to humans) with little success in the 17th century. The first documented transfusion of human blood was made in 1818 by Blundell, an obstetrician in London, who recognized the need for transfusion in women suffering from postpartum hemorrhage. His results were not reproducible owing to the lack of knowledge of blood types and anticoagulants.

Major advances were made in the beginning of 20th century when Landsteiner identified blood groups A, B, and C (later renamed group O ). Transfusion of fresh whole blood was reported as a treatment for epistaxis due to thrombocytopenia in 1910. Storage and distribution of donated blood became possible after sodium citrate was developed as an anticoagulant during World War I. The infrastructure of the modern blood banking system was established by World War II; use of fresh whole blood transfusion saved many wounded soldiers. However, the risk of pathogen transmission, including hepatitis via blood transfusion, was recognized later.

During World War II, Cohn and colleagues developed the cold ethanol method to separate albumin, γ-globulin, and fibrinogen from plasma, which became the basic principle for commercial plasma fractionation. Pooling of random donor plasma to manufacture factor (F) VIII concentrates without effective donor screening or virus inactivation steps in the late 1970s and early 1980s led to transfusion-related transmission of viruses, particularly human immunodeficiency virus (HIV) and hepatitis C to a large number of hemophiliac patients worldwide. Many precautions for blood-borne pathogens have been implemented, including vapor heat treatment and nanofiltration, since the mid-1980s; recombinant coagulation factors became available in the 1990s. The risk of infectious transmission also fueled efforts to develop synthetic oxygen carriers.

Over the years, clinicians have recognized the importance and potential harms of blood component therapies, fostering the creation of patient blood management programs. Preoperative anemia management is a critical part of patient blood management; iron supplementation and/or erythropoietin therapy can be used in appropriate patient groups. Perioperative cessation of antithrombotic agents, intraoperative blood salvage, and antifibrinolytic therapy are also utilized to minimize the need for allogeneic blood transfusion along with point-of-care coagulation monitors. The rational and cost-effective uses of blood components are now the subject of published transfusion guidelines.

Packed Red Blood Cells

Circulating red blood cells (RBCs) are anuclear, hemoglobin-carrying cells of about 7 to 8 µm in diameter. The biconcave and discoid shape of RBCs confers advantages in increasing surface area for gas exchange and flexibility in passing through capillaries. On average, RBCs remain in the circulation for 120 days. Senescent or abnormal RBCs are eliminated by the spleen. The synthesis of RBCs (erythropoiesis) is regulated by erythropoietin, which is elevated in anemia and hypoxia. Erythropoiesis is also affected by the availability of iron, an integral component of hemoglobin.

Packed RBCs (PRBCs) are prepared by separating most plasma components of donated whole blood by centrifugation. One unit of RBCs collected in anticoagulant-preservative solution is about 300 mL with a hematocrit of 50% to 70%. Dextrose is added to maintain glucose metabolism, and adenine and phosphate allow synthesis of adenosine triphosphate (ATP; Table 44.1 ). Additive solutions (adenine, glucose, mannitol, sodium chloride) are also used to extend shelf life up to 42 days. Depending on the storage solution, RBCs have a shelf life of 28 to 42 days at 1°C to 6°C. During storage, intracellular 2,3-diphosphoglycerate (DPG) is reduced to < 10% of normal at 5 weeks such that release of oxygen from hemoglobin is significantly impaired ( Fig. 44.1 ). Nonetheless, no differences in morbidity and mortality were detected between short-term storage (6–11 days) and long-term storage (21–28 days) in prospective randomized studies in premature infants, adult cardiac surgical patients, and critically ill adult subjects.

Clinical Uses

Transfusion of RBCs is indicated to restore the oxygen-carrying capacity in patients with severe anemia or major blood loss. There is no absolute level of hemoglobin that indicates a threshold for transfusion (“transfusion trigger”); underlying clinical conditions and laboratory data for each patient should be considered. Acute anemia is less well tolerated compared to chronic anemia, in which peripheral oxygen delivery is compensated by elevated 2,3-DPG levels in RBCs and higher cardiac output (see Fig. 44.1 ). In patients with moderate to severe cardiovascular dysfunction, anemia might not be well tolerated. The extent and duration of clinical bleeding are also important criteria for transfusion in major trauma and surgery. According to the American Society of Anesthesiologists (ASA) guidelines for blood component therapy, transfusion of RBCs is almost always indicated for hemoglobin less than 6 g/dL, whereas it is rarely indicated for hemoglobin greater than 10 g/dL. For hemoglobin between 6 g/dL and 10 g/dL, transfusion should be considered if complications due to inadequate oxygenation are anticipated. It remains controversial as to whether liberal or restrictive transfusion strategy is preferable in various surgical and medical settings. Restrictive transfusion (hemoglobin triggers < 7–8 g/dL) appears to increase mortality and ischemic events relative to a liberal strategy (triggers < 9–10 g/dL) in cardiovascular surgery patients and elderly orthopedic surgical patients. There was no difference in adverse event rates between liberal and restrictive strategies in nonsurgical critically ill patients.

ABO and Rh blood group–specific packed RBCs should be administered whenever possible ( Fig. 44.2 ). In the case of life-threatening hemorrhage without time for formal cross-matching, either Rh-positive or Rh-negative group O RBCs can be transfused in principle. In Rh-negative women of childbearing age, Rh-negative group O RBCs should be preferred for reducing the risk of alloantibody (anti-D) development, which can cause anemia in an Rh-positive fetus. Transfusion of mismatched RBCs, typically related to ABO, can induce immunoglobulin M (IgM) antibody–mediated acute hemolysis, but in less serious mismatches of minor antigens such as Rh, Kell, and Duffy, survival of transfused RBCs is shortened.

Erythropoietin

Erythropoietin is a hormone produced in the kidney in response to hypoxemia, such as in chronic pulmonary disease and at high altitudes. Recombinant human erythropoietin products are available for intravenous (IV) or subcutaneous (SC) injection. The primary indication for recombinant erythropoietin is anemia associated with chronic renal insufficiency. Other indications for erythropoietin include treatment of anemia related to the antiviral zidovudine in HIV-infected patients and treatment of chemotherapy-induced anemia in patients with metastatic, nonmyeloid malignancies. Preoperative erythropoietin treatment of anemia has been shown to reduce allogeneic RBC transfusion, but its high cost hinders easy access for perioperative anemic patients. There are a variety of perioperative dosing regimens in conjunction with iron supplementation. One example is a weekly dose of 600 units/kg SC started 3 weeks before surgery and the 4th dose given on the day of surgery. A single dose of 80,000 IU SC dose 2 days before cardiovascular surgery reduced the overall transfusion rate from 39% to 17% in a prospective randomized placebo-controlled study involving 600 patients.

Blood Substitutes

The limited availability of blood and infection risks are the driving forces in developing oxygen-carrying blood substitutes. Two major classes of substitutes are hemoglobin-based oxygen carriers (HBOC) and perfluorocarbon (PFC) emulsions. Bovine-derived hemoglobin glutamer-200 (Oxyglobin, Biopure, Cambridge, MA) is currently approved for canine anemia in the United States. In South Africa, bovine hemoglobin glutamer-250 (Hemopure, Biopure, Cambridge, MA) is approved for treatment of human anemia. Free hemoglobin solutions have a higher affinity for oxygen compared to RBCs (P ₅₀ of 12–14 mm Hg for HBOC vs. 27 mm Hg for RBCs). The modification of hemoglobin by pyridoxal phosphate increases P ₅₀ to 32 mm Hg, improving release of oxygen. Potential benefits of HBOCs include sparing allogeneic RBC transfusion in anemia, trauma, and major surgery, and reduction of transfusion-related infection and other complications. Compassionate use of HBOC has been reported in a Jehovah's Witness patient with acute lymphoblastic leukemia who survived severe anemia (lowest hemoglobin, 3.1 g/dL). However, vasoconstrictive properties of HBOC remain a major concern for further clinical development.

PFC emulsions consist of halogen-substituted hydrocarbons that enhance plasma oxygen solubility. Hydrophobic PFC molecules are dissolved in plasma using emulsifiers. Unlike hemoglobin, the oxygen-carrying capacity of PFC is directly proportional to oxygen partial pressure. Febrile reactions or flu-like symptoms can occur as PFC emulsion is taken up by the reticuloendothelial system. PFC is not clinically available at present, but potential perioperative uses include acute lung injury and acute normovolemic hemodilution to spare RBCs from extracorporeal circuits.

Albumin

Albumin is a 69-kDa plasma protein synthesized in the liver and present in plasma at 3 to 5 g/dL (~60% of plasma protein). Plasma-derived, pasteurized (60°C for 10 hours) fractions are available in iso-oncotic (5%) or hyper-oncotic (25%) solutions. Albumin exerts oncotic activity (colloid osmotic pressure) to retain intravascular water. The oncotic pressure of 5% albumin is equivalent to plasma. Albumin also serves to carry poorly water-soluble molecules (apoprotein, bilirudin, transferrin, and so on) and can bind a number of drugs. In hypovolemic patients, there is no evidence that albumin reduces mortality compared with crystalloid or colloid solutions. There are a few indications for albumin use, including fluid replacement for hypovolemic shock with lack of response to crystalloids or colloids, priming for extracorporeal circuits, and plasma exchange therapy. In acute liver failure, albumin can be used to restore oncotic pressure. The intravascular retention of albumin is affected by increased vascular permeability (e.g., first 24 hours of thermal injury) and excretion (e.g., nephrotic syndrome). Albumin does not affect hepatic or renal function.

Synthetic Colloids

Synthetic colloid solutions include hydroxyethylstarches (HESs), in which rapid degradation by α-amylase is prevented by hydroxyethylation of glucose subunits ( Fig. 44.3 ). The molar replacement ratio indicates the proportion of glucose molecules replaced with hydroxyethyl units (e.g., 0.4 = 40% replacement). The C2/C6 ratio indicates the number of hydroxyethyl units at the C2 relative to the C6 position. HES with higher molar replacement and C2/C6 ratios is retained longer owing to slower metabolism ( Table 44.2 ). HES is excreted by the kidneys after degradation.

Differences between albumin and HES in efficacy and safety are controversial. HES products are available in iso-oncotic (6%) or hyper-oncotic (10%) solutions. The most commonly used are 6% HES solutions, with an average molecular weight of 600 to 670 kDa (Hespan, Hextend, B. Braun, Bethlehem, PA), but low-molecular-weight HES (130 kDa, Voluven, Fresenius Kabi, Halden, Norway) has recently become available in the United States. HES products are as effective as albumin as fluid replacements, but large doses of HES (particularly, Hespan) can adversely affect coagulation (fibrin polymerization) and exacerbate renal dysfunction in sepsis. Excess HES can falsely elevate turbidometric fibrinogen measurements. Recently, the European Medical Association has recommended suspending marketing authorization for HES colloids in patients with sepsis or at risk for renal insufficiency. Colloid replacement therapy might still be indicated in early volume resuscitation after acute blood loss (e.g., trauma).

Platelet Concentrates

Platelets are anuclear, granulated cells 2 to 4 µm in diameter derived from bone marrow megakaryocytes. The normal half-life of platelets is 7 to 10 days. There are 150 to 350 × 10 ⁹ /L platelets in the circulation, but their concentration near arterial vessel walls is significantly higher owing to the margination of platelets by larger RBCs. Platelets rapidly respond to disruption of normal endothelium, contributing to the initial arrest of bleeding (primary hemostasis), and support of localized thrombin generation and fibrin formation (secondary hemostasis or coagulation; Fig. 44.4 ).

Since the first platelet transfusion in the 1950s, platelet concentrate remains the mainstay therapy for thrombocytopenia. Platelet concentrates are prepared by centrifugation of citrated whole blood within 8 hours of collection. After separating RBCs from platelet-rich plasma, further centrifugation yields 1 unit of platelet concentrate and plasma. Each unit of platelets, referred to as random-donor platelets , contains 5.5 × 10 ¹⁰ platelets in 50 to 70 mL of plasma. Four to 8 random-donor units are pooled to increase platelet count by 5 to 10 × 10 ⁹ /L in the adult. In order to decrease multiple donor exposures, single-donor platelet apheresis is increasingly used. During the apheresis procedure, donor blood is placed in the extracorporeal circuit and centrifuged to separate platelets. One platelet apheresis unit contains 30 to 50 × 10 ¹⁰ platelets in 250 to 300 mL of plasma. Platelet concentrates are agitated and stored at room temperature (20–24°C) for up to 5 days (see Table 44.1 ).

Clinical Uses

Platelet transfusion is used to prevent or treat bleeding due to platelet dysfunction or thrombocytopenia. Hereditary platelet dysfunction is rare, but adhesion defects in Bernard-Soulier syndrome (GPIb/IX deficiency), aggregation defects in Glanzmann thrombasthenia (GPIIb/IIIa deficiency), and a secretion defect in Hermansky–Pudlak syndrome (lack of dense granules) are prototypical hemorrhagic conditions resulting from decreased primary hemostasis. Platelet dysfunction in perioperative patients is usually due to antiplatelet therapy (see Chapter 45 ). Platelet transfusion can be required even with a normal platelet count if platelet dysfunction is clinically suspected or identified by platelet function testing.

Perioperative platelet dysfunction is most commonly caused by acetylsalicylic acid (aspirin), thienopyridines, or GPIIb/IIIa inhibitors. For thrombocytopenia associated with bone marrow disorders, prophylactic platelet transfusion for a threshold below 10 × 10 ⁹ /L appears to reduce the risk of serious bleeding events. The recommended thresholds for platelet transfusion for nonbleeding, critically ill patients are also in the similar range (10–20 × 10 ⁹ /L). The trigger platelet count usually falls in the range of 50–100 × 10 ⁹ /L in trauma or major surgery. The trigger values are generally higher for neurosurgical and cardiovascular procedures (> 100 × 10 ⁹ /L). For other procedures, such as lumber puncture or central venous catheterization, a threshold of platelet count between 20 and 50 × 10 ⁹ /L is used, but supporting evidence is rather weak.

Platelet transfusion is administered to mitigate microvascular bleeding due to thrombocytopenia or platelet dysfunction, but hypofibrinogenemia and hyperfibrinolysis need to be addressed separately as the latter are important causes of perioperative bleeding. It is often difficult to quantify hemostatic efficacy of platelet transfusion in the presence of multifactorial factor deficiency after major trauma or surgery. Platelet count does not reliably reflect functional recovery in the presence of platelet inhibitors and other pathologic conditions (e.g., extracorporeal circuit) that adversely affect platelet function. The timing and amount of platelet transfusion can be individualized using platelet function testing and/or thromboelastometry/thromboelastography ( Fig. 44.5 ). Modified thromboelastometry/thromboelastography assays suitable for monitoring antiplatelet agents have been developed, but further clinical validations are warranted for the standardization and optimal thresholds for transfusion.

Plasma

Plasma transfusion has been traditionally performed using fresh frozen plasma (FFP). FFP is prepared from whole blood (~500 mL) or apheresis donations and frozen at –18°C within 8 hours of collection. However, other plasma products have been increasingly used to make up the shortfall in plasma supply in the United States. Plasma frozen between 8–24 hours of phlebotomy (FP24) is a unit of plasma containing similar factor levels to FFP except for factor VIII (FVIII, up to 20% reduction). Each unit of FFP or FP24 is approximately 200 to 250 mL, and contains all components of donor plasma, including procoagulant and anticoagulant factors, albumin, and immunoglobulins. The recovery of coagulation factors after each plasma unit is about 2% to 3% in the adult but can vary with donors, clinical hemorrhage, and/or ongoing consumption. Plasma products can be stored frozen up to 12 months. Thawed plasma (FFP and FP24) are maintained in the liquid state for up to 5 days at 1°C to 6°C for clinical use, but some degradations of plasma factors do occur, particularly for FV and FVIII. Donor plasma should be compatible with recipients’ ABO types (see Fig. 44.2 ), but Rh types do not need to be considered. Blood group AB and A plasma have been used as universal donors for emergency.