A 7 year old boy is being worked up for profound pancytopenia. He was well until one week ago when his grandparents noted pallor. He has had no recent history of fever, and is otherwise well. He was initially seen yesterday in the hematology clinic, where a CBC showed a hemoglobin of 5.3 g/dl, WBC 1.9 K/ml with 96% lymphocytes, and a platelet count of 4,000. He has a bone marrow aspirate scheduled for tomorrow. He is brought back in to the clinic today, because he has epistaxis, which has been ongoing for 1 hour now. He states he feels weak and dizzy.

Exam: He is afebrile, BP 110/40, HR is 186 with a mild gallop. Weight is 26 kg (75%ile). He is lying down, with a tissue to his nose, and bright red blood is dripping out. He is alert and oriented, nontoxic, and comfortable. He is pale appearing, conversing appropriately, and no other overt bleeding is noted. His abdomen is benign.

CBC today shows hemoglobin 5.1, WBC 1.3, and platelet count 5,000. After IV access is obtained, he is given a fluid bolus and a "type and hold" for blood status is ordered.

The start of transfusion medicine occurred during World War II when the major blood types A, B, AB and O, and Rh factor were identified. Type A persons have A antigen on the membrane of their red blood cells. They develop anti-B antibodies shortly after birth without any prior antigenic stimulation, thus these antibodies are called natural antibodies. Type B persons have B antigen on the membranes of their red blood cells, and such persons naturally have anti-A antibodies in their plasma. Type AB persons have both A and B antigens, and no anti-A or anti-B antibodies in their plasma. Type O persons, who lack these major red cell membrane antigens, have both anti-A and anti-B antibodies. When crossmatching a unit of blood for a transfusion, the biggest concern is to avoid giving the patient antigen that would react with their own antibodies. Thus, people with type O blood are considered to be universal donors, with regard to red blood transfusions, since there are no major (A or B) antigens on their red blood cells.

Most transfusions of red blood are given as packed red blood cells (PRBCs) that have most of the plasma removed. Each unit of PRBCs is about 250 ml, depending on the type of preservative used, and each ml provides 1 milligram of elemental iron. The fastest rate of transfusing a patient should be 5 ml/kg/hour. Generally, a transfusion is ordered as 10-15 ml/kg given over 2 to 3 hours.

The advent of platelet transfusions in the early 1970's changed the survival rate for many diseases. Today, single donor platelets are usually considered the optimal product for most platelet transfusion needs. A single donor unit of platelets is based on the adult dose and contains about 225 ml per unit. It is obtained via pheresis from one donor and takes about 4 hours to donate, compared to 30 minutes to donate one pint of whole blood. Platelets extracted from a unit of whole blood (called random platelets) contain about 50 ml per unit. Usually about 6-8 random units (i.e., 6-8 different donor exposures!) need to be pooled together to equal the volume of one unit of single donor platelets. Single donor platelet transfusions are usually given over 1 hour.

A hemolytic transfusion reaction results when an antibody-antigen reaction causes (donor) red cell lysis. It is most severe when a patient has circulating antibody that reacts with donor antigen (RBCs). Some antigens produce stronger hemolytic reactions than others. For example, transfusion reactions involving A and B antigens will cause a brisk, severe hemolysis, leading to fatalities from renal failure. The Duffy and Kell antigens also cause significant hemolysis. The Lewy antigen leads to a mild hemolysis that is not usually fatal (remembered by the mnemonic Duffy dies, Kell kills, and Lewy lives). There are many other less common antigens, natural and acquired, that are screened for in the direct antibody test (DAT) during crossmatching. A patient having a hemolytic transfusion reaction may present with lower back pain, and hemoglobinuria. The treatment consists of supportive care, especially intravenous hydration to help protect the kidneys from damage. Corticosteroids may also be beneficial.

Another type of transfusion reaction is associated with urticaria, or less commonly, fevers. These reactions are typically caused by extraneous donor proteins, which are foreign to the recipient. These proteins are usually carried in the plasma of the donor product. Therefore, such reactions are usually seen more often with platelet transfusions than with red cell transfusions, since the platelet products carry more plasma than the packed red cell units. Urticaria reactions are usually mild, and treated with diphenhydramine and sometimes IV corticosteroids. Epinephrine is only rarely required. Fevers are usually mild and self-limited, and can be managed with acetaminophen.

Irradiation of blood products will inhibit the replication of nucleated cells (e.g., WBCs) in the donor product, by damaging their DNA. This radiation dose will not kill common organisms known to contaminate blood products. All transfusion products have donor stray white blood cells, which, in theory, could replicate when transfused into an immunocompromised host. This would cause a graft versus host (GVH) situation, which, when arising from a blood transfusion, is often fatal. Therefore, all blood products given to infants, oncology patients, or other immunocompromised hosts should be irradiated. The exception, of course, is a stem cell product for a stem cell (bone marrow) transplant. If these stem cells were irradiated, the new graft would not grow, and there would be no transplant.

Infusion filters should be used for all transfusions of packed red blood cells and platelets. The only exception to this is the infusion of a stem cell product for any type of stem cell transplant. There are many types of filters. Their main purpose is to filter out either extraneous white blood cells or large foreign proteins. The use of a filter during a transplant of stem cells would filter out the very stem cells that are intended for the patient! Since filters will not dependably remove all white blood cells, filters cannot replace irradiation to prevent graft versus host disease.

Infections acquired from transfusions are rare due to improved screening methods by blood banks. Infectious agents that can be transmitted through transfusions include HIV, Hepatitis B, Hepatitis C, Parvovirus and malaria. Blood is actively screened for all these agents and discarded if contamination is even suspected. Cytomegalovirus (CMV) infection can also be transmitted through blood transfusions. It is harbored in a dormant state in the white blood cells of previously infected persons. Since 80% of most adult populations are positive for past CMV infection, most donated blood is CMV serology positive. CMV infection can be transmitted to severely immunocompromised persons with no prior infection. Such an incident might occur during a bone marrow transplant. Since newborns up to age 4 months are considered immunocompromised and have no previous CMV infection, all newborns receive CMV negative blood.

Clinicians should familiarize themselves with the options for ordering, holding, or preparing for a PRBC transfusion. A "draw and tag" should be ordered for a patient who might possibly need a transfusion during the hospital stay (but the probability of this is low). In this case, a blood sample is drawn from the patient and the patient is tagged with a special blood products identification bracelet which is matched to the specimen drawn and a set of labels which will be used on any blood products which might be ordered for the patient in the next few days. If blood products are required for this patient, they can be ordered from the blood bank. The blood bank will crossmatch the blood using the previously drawn and labeled specimen.

A "type and hold", also called a "type and screen", should be ordered for a patient who has a moderate likelihood of requiring a transfusion during the hospital stay. The patient is drawn and tagged as in the "draw and tag" procedure. Additionally, the patient's blood type and Rh are determined and a screening test is performed for unexpected antibodies and minor compatibility group profiling. Thus, the patient's blood type and Rh are known which saves some time in case a crossmatch is needed.

A "type and crossmatch" should be ordered when the patient will be getting a transfusion. The patient is drawn and tagged. The patient's blood type, Rh, and antibody screens are performed. A unit of blood is then selected for the patient and compatibility testing is performed with the patient's specimen and the donor unit's PRBCs. This unit is then held for the patient. This unit cannot be used for any other patient, so a "type and crossmatch" should only be ordered when a transfusion is highly likely.

In a true emergency with a rapidly hemorrhaging and hypovolemic patient, the time required for blood typing and crossmatching (20 to 30 minutes) may not be available. Transfusing with O negative PRBCs (if available) is the best emergency option. In the meantime, a type and crossmatch should be in progress. Type specific blood (the patient's type and Rh are known, but a crossmatch has not yet been performed) is sometimes useful until a crossmatch is completed.

There are many ethical issues which need to be considered when transfusing patients. Because of the rare possibility of morbidity and mortality from transfusions, written and informed consent must always be obtained before a transfusion is given. The patient (or patient's guardian) must be fully informed of the rare possibilities of infectious agents and transfusion reactions. Full consideration must be given to the necessity of a transfusion. In short, if spontaneous resolution of the problem (anemia, thrombocytopenia, or other morbidity in which a transfusion is thought to be beneficial) can be expected, or if alternative treatments exist, the transfusion should be avoided. When considering a transfusion, the actual morbidity and mortality from the underlying problem itself, without a transfusion, must be weighed against the rare problems that may result from the transfusion itself. Adult patients may refuse a transfusion for themselves, regardless of their reasons, even in the face of death (e.g., Jehovah's Witness patients). A parent may also refuse a transfusion for their child. However, if a physician strongly believes that a child has a life-threatening condition that can only be effectively treated with a transfusion of a blood product, the physician is obligated to take legal action.

Questions

1. In the case above, you decide to transfuse the 26 kg patient with both PRBCs and one unit of single donor platelets. Which is the best way to transfuse the PRBCs?
. . . . . a. Transfuse 2 units, each over 6 hours, with furosemide in between the units.
. . . . . b. Transfuse 1 unit over 3 hours
. . . . . c. Transfuse 390 ml over 4 hours
. . . . . d. Transfuse 260 ml over 2 hours

2. During the transfusion of platelets, this patient develops 3 small hives (urticarial lesions) on his back. Which is the correct response? No pre-medications were given.
. . . . . a. Continue the transfusion. Stop and medicate if more hives appears.
. . . . . b. Stop the transfusion. Give diphenhydramine and proceed when the hives clear.
. . . . . c. Stop the transfusion. Draw blood for type and cross to check the crossmatch for that unit. Give diphenhydramine, and proceed with the same unit when the hives clear, and if the repeated crossmatch is OK.
. . . . . d. Stop the transfusion. Give diphenhydramine and methylprednisolone, and proceed when the hives resolve.

3. During the transfusion of PRBC, the child starts to complain of lower back pain during the transfusion. What is most likely happening?
. . . . . a. A febrile reaction from donor white blood cells causing an inflammatory response.
. . . . . b. A hemolytic reaction involving donor antibodies to recipient red blood cells.
. . . . . c. A hemolytic reaction involving donor red blood cells and recipient antibodies.
. . . . . d. Recipient mast cell histamine release, stimulated by donor antigen presenting cells.

4. All of the following should be done with this complaint of lower back pain, EXCEPT:
. . . . . a. Consider IV corticosteroids.
. . . . . b. Hydrate with IV fluid bolus.
. . . . . c. Repeat crossmatch with unit of blood being transfused.
. . . . . d. Administer subcutaneous epinephrine.

5. Which of the following children should receive a transfusion of PRBC?
. . . . . a. A 2 year old with Hgb 2.8 g/dl (etiology unclear at the moment), HR 200, with gallop.
. . . . . b. A 2 year old Jehovah's Witness with Hgb 2.8 g/dl (etiology unclear at the moment), HR 200 with gallop.
. . . . . c. A 4 year old just diagnosed with Neuroblastoma, Hgb 6.8 g/dl, HR 134.
. . . . . d. A 13 year old girl, presents with butterfly rash on her face, has fevers, Hgb 6.8 g/dl, rales, splenomegaly, HR 156.
. . . . . e. All of the above

6. Irradiation of blood products:
. . . . . a. Will prevent donor white blood cells from proliferating in the recipient's body.
. . . . . b. Will kill many common infections that could be transmitted in extraneous donor WBC or plasma.
. . . . . c. Could, in theory, take the place of blood filters.
. . . . . d. Is very expensive and tedious, and therefore should be used in only selected cases.

7. An 11 month old boy weighs 7.5 kg, and has Fe deficiency anemia with a Hgb 2.2 g/dl. HR is 188. You decide to transfuse him. Which is the best way to transfuse him with PRBCs (checking the Hgb at appropriate intervals)?
. . . . . a. Transfuse 150 ml over 12 hours.
. . . . . b. Transfuse 2 half units, each over 4 hours.
. . . . . c. Transfuse 15 cc/kg, i.e. about 112 ml slowly over 6 hours, then start oral Fe.
. . . . . d. Transfuse slowly at <3ml/kg/hour, with subunits from a unit split in the blood bank, and discard the remainder of each subunit after 4 hours.

References

1. Wandt H, Ehninger G, Gallmeier WM. New strategies for prophylactic platelet transfusion in patients with hematologic diseases. Oncologist 2001;6(5):446-450.

2. Perrotta PL, Snyder EL. Non-infectious complications of transfusion therapy. Blood Rev 2001;15(2):69-83.

3. Kulkarni R, Gera R. Pediatric transfusion therapy: practical considerations. Indian J Pediatr 1999;66(3):307-317.

4. Heddle NM. Pathophysiology of febrile nonhemolytic transfusion reactions. Curr Opin Hematol 1999;6(6):420-426.

Answers to questions

1. b. Once a unit is spiked (IV infusion begun from unit bag), any uninfused blood must be discarded after 4 hours. Thus, the most time allowed for 1 unit to run is over 4 hours. Therefore, a unit may not be transfused over 6 hours. Giving 390 ml would give this patient 15 ml/kg, but giving this over 4 hours would be slightly too fast with such a low and fast falling hemoglobin. Additionally, it would expose the patient to a second donor, and half of the second unit would be discarded (wasted). Giving 262 ml means giving 1 unit (about 250 ml), and about 10 ml from a second unit (discarding the rest). Giving this over 2 hours would also be too fast as noted.

2. b. For just a few hives, it is not necessary to check the crossmatch of the blood, since this will detect antibodies causing hemolysis. Urticaria is not a hemolytic reaction. Usually diphenhydramine alone can resolve the hives, and the same unit can be continued with the diphenhydramine in effect.

3. c. See text

4. d. Epinephrine has no known beneficial effect on the hemolytic process.

5 e. All of these children should probably receive a transfusion.

6. a. See text

7. d. A unit of PRBCs can be split in the blood bank (like neonatal units) so that only one part of this is out of the blood bank and infusing into the patient at a given time (which can infuse up to 4 hours). Additionally, a child with such an extremely low hemoglobin needs to be transfused very slowly, at least initially, so as not to push his already compromised heart into further failure. With severe anemia, the patient is already in high output congestive heart failure. Blood is a potent volume expander which can suddenly worsen the CHF. Thus, the transfusion must proceed very slowly under close hemodynamic monitoring.