Blood component transfusion therapy (Proceedings)

Blood component transfusion is generally provided as supportive therapy for correction of one or more hematologic and/or hemostatic deficiencies, until the underlying disease process can be controlled or corrected. Blood component administration and its immediate endpoints often are only one part of a general therapeutic plan. Although appropriate endpoints may be achieved in terms of measurable parameters or clinical response, the clinician needs evidence that the traditional "outcomes" are relevant in relation to the final outcome for the patient. However, evidence-based support of many transfusion practices, in many clinical settings, is limited. Therefore, the clinician must base the administration of component therapy on good understanding of the problem in terms of pathophysiology and indicators of severity. Indiscriminate administration of blood products may pose unnecessary risk to the patient. The basic principles of component therapy are:

a. transfuse only what is needed

b. transfuse only when there is a clinically significant problem

c. weigh benefits, risks and alternatives to transfusion therapy

Compensatory mechanisms for anemia

Adequate oxygen supply is a key factor in maintaining body function and cell homeostasis. Therefore there is a normal physiologic response to anemia, which helps maintain this oxygen supply to the peripheral tissues. This physiological response to anemia consists of cardiac and peripheral tissue adaptations as well as changes in red blood cell (RBC) 2,3-diphosphoglycerate (2,3-DPG). Cardiac output (CO) is increased by an accompanying decrease in vascular resistance as viscosity decreases with anemia, in addition, increasing heart rate and/or stroke volume. As the heart normally extracts ~80 % of O2 delivered, increased cardiac O2 extraction is achieved largely by increasing coronary artery flow by coronary artery vasodilation. Animal studies suggest that lower limit of cardiac tolerance for anemia in the presence of normal cardiovascular system is in the hemoglobin (Hb) range of ~3-5 g/dL.

Peripheral tissue compensation for anemia is to increase O2 delivery by increasing blood flow through vascular beds, to recruit more capillaries, or in the case of supply-dependent tissues, to increase oxygen extraction. These compensatory mechanisms may, however, be limited and dependent on circulating intravascular volume as well as on red blood cell mass in the case of the splanchnic bed, muscles, and skin. With chronic anemia, RBC intracellular 2,3-DPG concentrations also increase, shifting the oxyhemoglobin dissociation curve to the right, thereby facilitating tissue off-loading of O2.

It should be noted that a Hb / Hct that is adequate in a stable setting, may no longer by adequate in the same patient in a stressful postoperative setting, ie. awake, shivering, in pain, with a systemic inflammatory response after surgery. A recent study in Jehovah's Witnesses indicates that postoperative morbidity and mortality begin to rise when the Hb is < 5 g/dL in patients without cardiovascular compromise.

The decision to transfuse should be supported by the need to relieve clinical signs and symptoms of impaired oxygen transport and to minimize morbidity and mortality. The question of the lowest safe hematocrit continues to remain unanswered and likely varies between different patient species, breed, comorbidities and underlying pathophysiologic states.

Red blood cell transfusions

In critically ill patients, decreased CO, decreased RBC mass and acidosis can impair O2 delivery and tissue use of O2. Administering RBCs may enhance O2 delivery to tissues. However, some investigators have found a significant association between RBC transfusion and increased mortality in human ICU patients; transfused patients had longer ICU stays, more severe organ failure, and higher mortality rates than non-transfused patients. Although these associations may be explained by different underlying clinical conditions and altered or blunted erythropoeitic responses that are characteristic of anemia of inflammation (chronic disease), attendant risks of RBC transfusion include febrile, nonhemolytic transfusion reactions, immunosuppression and alloimmunization. Using newer, rather than older, RBCs (ie. RBC stored for fewer than 15 days) and leukocyte-depleted, rather than non-leukocyte-depleted, RBC products may provide important benefits.

Most blood transfusions are allogenic (collected from one individual and administered to another of the same species). Some units of whole blood (WB) are administered as such, but most are separated into 2 or more components – one unit of packed RBCs (pRBCs), one unit of plasma, and sometimes one unit of donor platelets. The plasma may be further separated into one unit of cryoprecipitate and one unit of cryopoor plasma. Most RBC units contain an additive solution that improves viability and shelf life.

In WB donation, a canine unit is 450-500 mls and feline unit is 55-60 mls and are typically collected in citrate-based anticoagulant, contained in a sterile, plastic bag. Vacuum bottles have fallen out of favor due to the inability to separate blood components, activation of platelets, potential for air embolism and bottle breakage. In contrast, plastic bags allow easy separation of blood components and are generally less expensive. Fresh WB contains all cellular and protein blood constituents, and is administered within 6 hours of collection. Once the first 12 hours have passed, labile coagulation protein activity (specifically factors V and VIII) start to deteriorate and cannot be relied upon. Blood not administered within 6 hours of collection, should be stored in a refrigerator (1-6ºC).

Clinical indications for administration of fresh WB are severe hemorrhage induced hypovolemic shock, hemorrhage secondary to thrombocytopenia, thrombocytopathy, coagulapathy (including hemophilia), or von Willebrand disease (vWd). Use of fresh WB lacks the concerns of "storage lesions" (see table) and provides fully functional RBCs. Clinical indications for use of stored WB include severe hemorrhage induced hypovolemic shock from trauma, neoplasia or vitamin K antagonist toxicity. while it is an inferior alternative to fresh WB for use in hemorrhage secondary to thrombocytopenia, thrombocytopathy, hemophilia or vWd. With the latter two conditions administration of fresh frozen plasma is likely to be necessary to help eradicate the source of hemorrhage. Whole blood storage time is up to 35 days if collected in citrate-phosphate-dextrose-adenine (CPDA-1) and stored in a refrigerator (1-6ºC).

When plasma and platelets are removed, a 450-500 ml canine unit is reduced to 220-250 mls of packed pRBCs, and the Hct is about 80%. With the addition of a preservative solution (ie. Adsol, Nutricell), the volume is increased to 320-350 mls and the Hct drops to about 60%. Thus, canine pRBCs typically contain a preservative solution (saline, adenine, dextrose) as well as about 25 mls of remaining plasma. Feline pRBCs typically have a Hct that varies between 45-60%. Despite the presence of a preservative, RBCs undergo biochemical and physical changes in vitro, referred to as "storage lesions" (see table). Most storage lesions are reversible following transfusion, although it may impose excessive metabolic demands on a critically ill patient. The clinical indications for the administration of pRBCs are typically anemia secondary to chronic hemorrhage, immune-mediated RBC destruction or primary bone failure. The smaller volume, compared to whole blood, minimizes the risk of volume overload during administration. Packed RBC storage time is up to 42 days (with addition of preservative) stored in a refrigerator (1-6ºC).

All blood components should be warmed prior to administration. Warming RBC products reduces viscosity and increases infusion rate. However, the main reason for warming blood is prevention of hypothermia in the recipient. Generally RBC bags ware warmed by protecting them in a sealed plastic bag and submerging them in warm water (not exceeding 37ºC to prevent thermal RBC injury). However, when time is limited, the blood administration line can be placed in a warm water bath. All cellular blood components must be administered through a standard blood filter (170-260 microns) to remove any aggregates that may have formed during storage. These filters can become an impediment to flow as they collect trapped debris, and thus they may need to be replaced periodically, especially if blood clots had formed in the unit after collection.

Autologous blood collection or autotransfusion are alternatives to allogenic blood transfusion therapy. The former is available in several forms (acute normovolemic hemodilution, preoperative autologous blood donation, etc.) and is typically limited to patients that are knowingly going to experience a procedure that may predispose to substantial hemorrhage (adrenalectomy involving large vascular invasion, etc). These procedures will require all of the same precautions (blood filter, etc) that autologous units require. Collection of free blood from the thoracic or abdominal cavity is considered devoid of platelets and fibrinogen and relative contraindications to their use are contamination with infectious agents or neoplastic cells. However, intact RBCs are immediately available for O2 transport. Using recombinant erythropoietin offers an alternative to RBC transfusion and is being evaluated in more detail at this time.

When administering RBCs to a patient, one can estimate the amount of product needed by the following calculation:

The blood volume in canines is 80-90 ml/kg and felines is 50-60 ml/kg. The other rule of thumb for amount to be administered is 20 ml/kg of WB will increase the PCV by 10%, whereas 10 ml/kg of pRBCs will increase the PCV by 10 %. These calculations will vary with age of the units administered as older units have a lower yield of RBCs 24 hours post-transfusion. Expiration dates assume proper storage and handling, and are typically based on recovery of 75% of the RBCs administered, 24 hours after completion.

Plasma transfusions, cryoprecipitate, cryofree plasma

Clinically, spontaneous bleeding is rare in isolated factor deficiencies unless levels are < 5% of normal. Under conditions of stress (surgery, invasive procedures) bleeding often occurs when factor levels start to fall below 20-30%, particularly in complex coagulopathies. Global measures of coagulation (prothrombin time - PT/ partial thromboplastin time - PTT) normally are used for clinical assessment. Although sensitivity to factor deficiencies is reagent-specific, in general the PT and PTT do not prolong until factors are <30-40% of normal. Plasma should not be used as a volume expander, a nutritional supplement, or for non-urgent correction of vitamin K deficiency.

Indications for plasma include urgent correction of multifactorial coagulopathy when the PT and/or PTT are >1.5 normal. Plasma dosing of 20 ml/kg usually will restore coagulation factor levels to 30% in stable, nonbleeding patients. Although plasma frequently is administered to correct mild prolongations of the PT (>1.2-1.5) and PTT (>1.2-1.5) before invasive procedures, there is little evidence to support this practice, and the skill of the operator doing the procedure is more predictive of bleeding. It also should be noted that increasing the coagulation factors by 10% will have a significant impact on the PT and PTT when they are prolonged > 2 times midrange normal but will have only a minimal effect on more modest prolongations. It is difficult to correct coagulopathy of severe liver disease with plasma because the short half-life (6 hours) of factor VII makes it difficult to infuse the product quickly enough.

Fresh frozen plasma (FFP) is plasma that is separated from fresh whole blood and frozen within 6 hours of collection. Fresh frozen plasma contains normal levels of all coagulation factors, natural inhibitors, and plasma proteins (albumin, immunoglobulins). Canine FFP volume is approximately 200-225 mls, and shelf life is 1 year if frozen at -18ºC.

Frozen plasma (FP) is plasma that is prepared more than 6 hours after blood collection or FFP stored beyond its 1-year shelf life. FP contains minimal amounts of factors V, VIII, and von Willebrand factor (vWf). FP has a total shelf life of 5 years from the collection date.

Cryoprecipitate (Cryo) is prepared when ultrafrozen (-70ºC) FFP is slowly and partially thawed between 1-6ºC (refrigerator temperature), producing a white precipitate, which is harvested and then refrozen. Cryo contains fibrinogen, factor VIII, factor XIII, and vWf. Therefore, therapeutic use is generally reserved for patients with hypofibrinogenemias (massive transfusion or DIC), hemophilia A or vWd unresponsive to DDAVP. Cryo volume is generally 1/10th of the original plasma unit. Shelf life is identical to FFP, but once thawed, cryoprecipitate keeps only 4 hours at room temperature.

Cyrofree plasma is the plasma that remains after cryoprecipitate has been harvested from FFP. Cryofree plasma therefore contains albumin, all vitamin K-dependent coagulation proteins and anti-coagulant proteins. Clinical indications for use include vitamin K antagonist toxicity, colostrum replacement and hypoproteinemia. Cryofree plasma has an expiration date of five years from the time of blood collection. Volume is typically under 200 mls.

It is important to understand that frozen components are fragile and cracking of the collection bag is possible if not handled carefully. Therefore it is recommended to thaw all frozen products in the box that the product is received in. The unit may then be removed once thawed. Before thawing, the unit and box should be placed in a watertight, sealed, plastic bag to avoid contamination of the spike ports. Once blood products have been warmed to room temperature, they should be administered within 4-6 hours to minimize the risk of bacterial proliferation and subsequent infectious complications in the recipient. Blood products that have been thawed at or maintained at refrigerator temperature may be used over 24 hours, once the bag has been entered. Therefore, if one anticipates that administration of the unit will require more than 4-6 hours, then the sample should be aliquoted into smaller volumes. Each smaller aliquot may then be independently brought to room temperature and administered. Dilution of blood products (ie. pRBCs) should be accomplished with a non-calcium containing, isotonic solutions (ie. avoid lactated ringers solution).

Platelet transfusions

Platelet transfusions are not routinely administered in veterinary patients due to cost, short shelf-life and lack of availability. Platelets may be given both prophylactically and therapeutically or to assure effective hemostasis during surgery or other invasive procedures (biopsies, thoracocentesis, etc). Spontaneous bleeding is rare at platelet counts 10-25,000/ul providing that platelet function is normal and no concomitant hemostatic defect exists. Platelet counts of 40-50,000/ul of functional platelets, in the absence of other coagulation defects, are usually enough to assure hemostasis. In patients with qualitative defects in platelet function, platelet count is not a reliable indicator of transfusion, and transfusion decisions and monitoring efficacy must be based on the setting and clinical features. Platelet-rich plasma is suspended and frozen in dimethyl sulfoxide (DMSO) and stored for up to 6 months. Due to severely shortened life span, the transfusion of platelet concentrate is not generally considered appropriate when thrombocytopenia is due to immune-mediated destruction.

Albumin products

Both human and canine albumin products are available. Unlike other blood products, these come in glass bottles and must be vented or placed into a syringe for IV administration. Human products are manufactured in a 5% solution (isotonic) and a 25% solution (hypertonic). The canine product is lyophilized, must be stored in the refrigerator and has a 3-year shelf life. Reconstitution may be performed to achieve various concentrations. Administration should occur through a filter and be completed within 24 hours. Species-specific albumin is preferred, when available. Concentrated albumin is most often administered to hypoalbuminemic patients and rarely used to restore intravascular volume.

Storage, anti-coagulant, preservatives

Red blood cell storage should occur in a refrigerator with limited activity and units stored toward the back. Periodic agitation of blood units during the storage interval can help enhance preservation of the RBCs. Frozen products should be kept in a freezer without automatic defrosting ability. Frozen products should also be initially frozen with a rubber band around the unit. Once the unit is frozen, the rubber band should be removed. Loss of a "waist" around the unit suggests that the unit was thawed (intentionally or accidentally) and may not be suitable for administration.

Heparin is an anti-coagulant with no preservative action, therefore heparinized blood should be administered within 6-8 hours of collection. Heparin also causes platelet aggregation and inhibits coagulation factors.

References Available Upon Request