Hospital Medicine

Transfusion medicine

Transfusion medicine

I. Problem/Condition.

Overview

The hospitalist is often faced with the decision of when to transfuse patients with blood components. Once it has been decided that transfusion support is necessary, the patient must be appropriately counseled about the risks and benefits of transfusion. Finally, the hospitalist must be aware of available blood components for appropriate utilization, common transfusion reactions and complications, and their management. This topic will succinctly cover indications for transfusion, risks of transmitting viral disease with transfusion and common non-viral complications of transfusion. Finally, the chapter ends with a list of "high-yield" transfusion-related facts meant to help hospitalists make decisions at the patient's bedside.

Indications for Transfusion

Reasons to transfuse vary based upon a patient's overall condition and comorbidities. However, some indications for transfusion are considered standard in the average patient. Most physicians consider the transfusion of platelets to be indicated when a patient has ongoing bleeding or will be undergoing an invasive procedure and has a platelet count below 50,000 (100,000 for a central nervous system or eye surgery) per microliter. If a patient does not have ongoing bleeding, platelet transfusion is usually indicated if the platelet count drops below 20,000 per microliter in the setting of fever. If a patient has no bleeding or planned invasive procedure and is afebrile, it is usually safe to forgo platelet transfusion unless the platelet count drops below 10,000 per microliter.

Infusion of fresh frozen plasma may be indicated in a patient with ongoing bleeding and an elevated prothrombin time or activated partial thromboplastin time to greater than 1.5 times the mean of the normal range. Infusion of cryoprecipitate (which contains fibrinogen, von Willebrand factor, and factors VIII and XIII) is most often indicated in the setting of disseminated intravascular coagulation with a fibrinogen level of less than 100mg/dL. FFP or factor concentrates can be used in the management of warfarin associated anticoagulation and INR reversal in patients undergoing invasive procedures or actively bleeding. Various institutions have established criterion for this purpose.

Great debate persists regarding indications for transfusion of packed red blood cells. A trial in resting human subjects demonstrated it is possible for adults without underlying medical illnesses to undergo isovolemic reduction in hemoglobin to 5 g/dL without failure of oxygen delivery due to their ability to increase cardiac output and decrease systemic vascular resistance. While this experiment proved an interesting physiologic principle, a study looking at a more diverse group of patients who underwent surgical procedures but refused transfusion support due to religious reasons began to show an increase in 30-day mortality in patients whose hemoglobin nadir was less than 7 g/dL.

In the perioperative setting, most experienced clinicians are now comfortable letting hemoglobin levels in asymptomatic patients without known cardiovascular disease drop as low as 7 or 8 g/dL before transfusing red blood cells. This practice is supported by the results of large retrospective cohort studies. More debate exists about what the goal perioperative hemoglobin level should be in patients with known cardiovascular disease. Traditionally, many experts have advised transfusing patients with known cardiovascular disease when their hemoglobin drops below either 9 or 10 g/dL.

A more definitive answer on whether this practice improves outcomes in patients with cardiovascular disease was gleaned from the results of a large prospective trial (the FOCUS trial) that looked at functional capacity at 60 days and postoperative myocardial infarction and death in patients with a history of or at high risk for cardiovascular disease who were anemic after surgical hip fracture repair and who were treated with different transfusion thresholds. Patients in the liberal transfusion strategy group were transfused when their hemoglobin fell below 10 g/dL. Those in the restrictive strategy group received transfusions only when their hemoglobin fell below 8 g/dL. At 60 days the liberal transfusion strategy failed to reduce rates of death, in-hospital morbidity or inability to walk independently.

A more recent multicenter, parallel-group trial (TITRe2 trial) compared liberal versus restrictive transfusion in nonemergent cardiac surgery patient suggested a reduction in morbidity and healthcare cost associated with liberal transfusion.

Outside of the perioperative setting, good data from a multicenter randomized controlled trial (Transfusion Requirements in Critical Care or the TRICC trial) exists that critically ill patients transfused when their hemoglobin drops below 10 have no better outcomes than patients transfused only when their hemoglobin levels drops below 7 g/dL. Interestingly, even patients with known cardiovascular disease failed to benefit from maintaining a hemoglobin of 10 g/dL in this trial.

Transfusion and the Risk of Infection

Many patients are hesitant to receive any form of transfusion support due to their fear of being infected with the human immunodeficiency virus or hepatitis C virus. Fortunately, the risk of acquiring such infections is now quite low (estimated to be about a one in two million chance for hepatitis C and also one in two million for HIV since nucleic acid testing of donor blood was introduced in 1999).

Rarely, bacterial infections can be transmitted via transfusion. Platelet units harbor pathogenic numbers of bacteria more frequently than other blood products due to being stored at room temperature. Most likely culprits associated with platelets transfusions are gram positive organisms. When red blood cells are contaminated, the organism is often Yersinia enterocolitica given its ability to survive cold temperatures. Transfusion-induced bacteremia can be difficult to distinguish from other transfusion complications such as acute hemolytic transfusion reactions and febrile nonhemolytic transfusion reactions. The approach to the patient having an adverse reaction to a transfusion is detailed below.

Other Transfusion-related Complications

Febrile Non-hemolytic Transfusion Reactions:

A febrile non-hemolytic transfusion reactions (FNHTR) is the most common adverse reaction seen with transfusion. Median reported rates for FNHTR are higher with the transfusion of platelets (about 5%) than with red blood cell transfusions (0.33%). A common definition for FNHTR is a temperature rise of more than 1 degree Celsius above baseline and/or rigors within 3 hours of starting a transfusion.

The main mechanisms that cause FNHTRs are thought to be the release of cytokines by leukocytes and other cells into blood products while they are stored (which are transfused into recipients along with the desired blood products) and cytokines that are released by leukocytes transfused into a recipient along with the desired blood product (usually red blood cells or platelets). Cytokines such as IL-1, IL-6 and TNF stimulate the anterior hypothalamus to produce prostaglandin E2 leading to fever.

Although FNHTRs almost never lead to longterm morbidity, they are often difficult to distinguish from more life-threatening transfusion reactions during their early presentation given their nonspecific symptoms (fever, chills and occasionally mild dyspnea). Unfortunately, this diagnostic uncertainty necessitates discontinuation of the transfusion and intensification of clinical monitoring of the patient. Treatment of a FNHTR is supportive with acetaminophen for fever or meperidine for severe rigors. Despite the common practice of "premedicating" patients with acetaminophen prior to transfusion, there is no good evidence that such treatment will prevent most FNHTRs.

Allergic Transfusion Reactions:

Like FNHTRs, allergic transfusion reactions are quite common and are more likely to be precipitated by platelet transfusion than red blood cell transfusion. Allergic transfusion reactions can also be precipitated by plasma or cryoprecipitate. There is a wide spectrum of severity within the diagnosis of allergic transfusion reaction ranging from a very benign reaction of pruritis or localized hives to severe, life-threatening anaphylaxis manifested by hypotension, wheezing or stridor.

Allergic transfusion reactions can be caused by allergenic substances in the plasma of donated blood products which interact with pre-formed IgE in the recipient. Another important mechanism for allergic transfusion reactions is that of preexisting IgG antibodies in the recipient that can react to an antigen in a transfused blood product. This mechanism is responsible for allergic transfusion reactions that can occur when a blood product containing any amount of IgA is transfused into a patient with severe IgA deficiency. Although IgA deficiency is common, fortunately most patients with IgA deficiency do not form anti-IgA antibodies.

Patients who have had an anaphylactic transfusion reaction should be screened for severe selective IgA deficiency and anti-IgA antibodies. Early recognition of potential transfusion needs is important in known IgA-deficient patients. If a patient has known severe IgA deficiency, they should be tested for preformed antibodies against IgA prior to any transfusion. If anti-IgA antibodies are present, the blood bank should be contacted and will usually help the treating physician decide whether special washed blood products or blood products from an IgA deficient donor should be obtained. If IgA-deficient blood is needed, it may take a few days to recruit the specific donors and to process the blood according to transfusion standards mandated by the United States’ Federal Drug Administration prior to transfusion. Management of allergic transfusions is described below.

Acute Hemolytic Transfusion Reactions:

Acute hemolytic transfusion reactions are covered in detail as a separate topic review and will only be discussed briefly here in the context of differentiating this type of transfusion reaction from the others discussed in this topic review. Acute hemolytic transfusion reactions are the result of transfusion of ABO mismatched blood which usually occurs in the setting of clerical error. Preformed IgM antibodies in the transfusion recipient that react against A or B antigens in donor blood fix complement and cause the rapid destruction of donor erythrocytes with ensuing hyperkalemia, pigment-induced renal failure, disseminated intravascular coagulation and shock. Clinical and laboratory findings and approach to management of acute hemolytic transfusion reactions are briefly detailed below.

Transfusion-related Acute Lung Injury (TRALI):

TRALI is covered in detail as a separate topic review and will only be discussed briefly here in the context of differentiating this type of transfusion reaction from the others discussed in this topic review. TRALI is seen when anti-granulocyte antibodies in the donor's plasma react with the recipient's granulocytes located in the pulmonary vasculature. Cytokine release causes increased vascular permeability which leads to noncardiogenic pulmonary edema. Respiratory distress and associated signs occur within 6 hours after transfusion. Respiratory symptoms that appear after 6 hours are less likely to be TRALI; in this scenario, pulmonary congestion associated with volume overload is the most likely the explanation. Clinical and radiographic findings and appropriate initial management of TRALI are covered briefly below.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

When a patient has a transfusion reaction, initially it can be difficult to distinguish which type of reaction they are experiencing. Nearly all of the transfusion reactions can present with signs of fever, tachycardia and tachypnea. However, with the performance of serial physical examinations, basic laboratory tests and a chest radiograph it should be possible to make a firm diagnosis of transfusion-related bacteremia, FNHTR, allergic transfusion reaction, acute hemolytic transfusion reaction or TRALI.

B. Describe a diagnostic approach/method to the patient with this problem.

A stepwise approach to diagnosing a transfusion reaction can help the clinician make an appropriate diagnosis.

  1. Stop the transfusion.

  2. Perform a focused physical examination and resuscitate the patient as needed (ABC’s). Assess the patient's airway and respiratory effort. Pursue immediate treatment with 0.3-0.5 mg of epinephrine IM if anaphylaxis is suspected in the setting of angioedema, wheezing, stridor or severe hypotension (see topic review on anaphylaxis for further recommendations). Administer normal saline via aggressive intravenous boluses for hypotension with subsequent initiation of treatment with vasopressors if hypotension does not respond to treatment with fluids.

  3. Call your Blood Bank to notify them of the transfusion reaction. They will help direct further workup.

  4. Collect a blood sample from the arm opposite that into which the transfusion was administered. Send it for Coomb's testing, plasma free hemoglobin, repeat type and cross match and bacterial culture.

  5. Start broad-spectrum antibiotics. Given that transfusion-transmitted bacteremia can be caused by either gram positive (coagulase negative Staphor Propionibacterium acnes) or gram negative (Yersinia enterocolitica, Serratia spp. or Pseudomonas spp.) pathogens, multiple antibiotics may need to be started initially and later de-escalated once a specific pathogen is identified (or a diagnosis other than transfusion-transmitted bacterial infection has been made).

  6. Send a urine specimen to be analyzed for free hemoglobin.

  7. Send the blood product bag to the microbiology laboratory where it can be evaluated for bacterial contamination, ABO/RH typing and antibody evaluation.

1. Historical information important in the diagnosis of this problem.

It is important to try to get a sense of the time relation between transfusion and a patient's symptoms. Whereas FNHTRs can occur up to several hours after transfusion, acute hemolytic transfusion reactions most often cause symptoms during or very shortly after transfusion. Allergic and anaphylactic transfusion reactions usually have a rapid onset during transfusion. Transfusion-transmitted bacteremia usually leads to symptoms during the transfusion although onset of signs and symptoms can be delayed in immunosuppressed patients who receive a smaller innoculum of bacteria. Symptoms of TRALI usually arise during or shortly after a transfusion (although they can sometimes be delayed up to 6 hours). Respiratory symptoms beyond 6 hours are less likely to be TRALI; in this scenario, pulmonary congestion associated with volume overload is the most likely the explanation.

Patients with an acute hemolytic transfusion reaction may complain of flank pain and a "sense of impending doom." Patients with TRALI will likely have dyspnea out of proportion to other symptoms.

Patients who develop an urticarial allergic reaction to transfusion may have a history of atopy. Patients who develop an anaphylactic reaction to transfusion should be questioned to look for signs or symptoms of selective IgA deficiency such as frequent sinopulmonary infections.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

As noted above, close attention should be paid to the patient's vital signs in order to perform an adequate resuscitation.

Special attention should also be paid to the pulmonary examination. Look for significant accessory muscle use or crackles on examination which suggest TRALI. If available, gross inspection of the patient's urine at the bedside might reveal brownish-red discoloration that is seen with hemoglobinuria.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

A positive direct Coomb's test, positive free hemoglobin, hyperkalemia, unconjugated hyperbilirubinemia and positive urine test for hemoglobinuria will be seen with an acute hemolytic transfusion reaction.

Blood cultures from the patient and the transfusion bag will often show microbial growth with transfusion-transmitted bacterial infection.

The patient with an anaphylactic transfusion reaction in the setting of a selective IgA deficiency will have a severe IgA deficiency on laboratory evaluation and evidence of pre-formed anti IgA antibodies. Both of these laboratory tests should be performed on any patient who has an anaphylactic transfusion reaction.

A B-type natriuretic peptide may be helpful if it is difficult to delineate whether a patient has TRALI or transfusion-associated circulatory overload (TACO).

The classic chest radiograph in TRALI reveals patchy bilateral alveolar infiltrates without cardiomegaly or pleural effusions.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Each diagnosis is made with a combination of the history, physical examination, laboratory data and chest radiograph as detailed above.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

NA

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem in Transfusion Medicine.

Management of Specific Transfusion Reactions

Transfusion-transmitted bacteremia should initially be treated with broad-spectrum antibiotics. Gram positive pathogens (including staphylococcus) and gram negative pathogens (including pseudomonas) should be covered. Culture results obtained from both the patient and the blood product bag can guide the eventual de-escalation of antibiotics. Treatment of transfusion-transmitted bacteremia is similar to treating bacteremia due to other more common causes.

FNHTRs are treated supportively with acetaminophen administered for fever and meperidine administered only for severe rigors. One FNHTR does not necessarily predict that a patient will have subsequent FNHTRs. However, some practitioners will secure blood that has been leukocyte-reduced for future transfusions for a patient who has had a FNHTR. There is no consensus on whether patients who have had prior FNHTRs should be premedicated with acetaminophen prior to future transfusions.

Allergic transfusion reactions can be broken down into anaphylactic transfusion reactions and urticarial transfusion reactions for means of determining appropriate treatment. Anaphylactic reactions to transfusion should be treated like anaphylaxis due to any cause. The mainstays of such treatment include 0.3-0.5 mg of epinephrine injected into the anterolateral thigh (with repeat doses or escalation to an intravenous infusion as determined by clinical response), placement of an advanced airway at the earliest signs of airway compromise, aggressive resuscitation with normal saline, administration of both H1 and H2 histamine receptor blockers and possible administration of corticosteroids (see specific topic review for further details).

Localized urticarial transfusion reactions should lead to temporary discontinuation of a transfusion to monitor the patient for development of a generalized urticarial rash or signs of angioedema or anaphylaxis. If the urticarial rash stays localized after a period of observation, the patient can resume the previously started transfusion after being medicated with diphenhydramine.

Acute hemolytic transfusion reactions constitute a medical emergency as they have a mortality rate of about 10%. The transfusion should be stopped immediately and the patient should be treated with an aggressive normal saline infusion to induce a diuresis. Evaluation for and treatment of hyperkalemia, acute renal failure and disseminated intravascular coagulation should be pursued. The patient should be monitored with telemetry for signs of arrhythmia. (See full topic review on acute hemolytic transfusion reaction for further details).

TRALI is treated supportively with supplemental oxygen or mechanical ventilatory support as needed. There is no clear role for treatment with diuretics or corticosteroids. Fortunately, TRALI often resolves within 2-3 days strictly with supportive care (see the full topic review on TRALI for further details on management strategies).

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

General Transfusion Medicine Pearls and Pitfalls

Plasma:

Fresh frozen plasma will not correct a coagulopathy caused by infusion of heparin. Protamine should be infused instead if heparinization needs to be emergently reversed due to acute hemorrhage.

One unit of fresh frozen plasma contains a significant amount of volume (200 mL) and close attention to the patient's volume status should be paid with plasma infusions.

If a patient who has a prolonged PT due to treatment with warfarin presents with bleeding but cannot tolerate the volume of a fresh frozen plasma infusion, consider treatment with prothrombin complex concentrate which contains factors II, VII, IX and X and can be infused in small volumes.

Fresh frozen plasma has a half-life of only 3-5 hours, so more definitive therapy (for example vitamin K for warfarin toxicity) should be administered concomitantly with FFP.

Fresh frozen plasma should be dosed based on a patient's weight rather than based upon results of coagulation studies alone. Dose at 10-15 mL/kg (3-4 units for an average-sized patient).

Cryoprecipitate:

Cryoprecipitate contains fibrinogen, factor VIII, von Willebrand factor (vWF) and factor XIII.

Cryoprecipitate can be used to replace fibrinogen or factor XIII that is consumed in DIC.

Cryoprecipitate may help overcome bleeding in the setting of uremia due to the factor VIII and vWF it contains.

Cryoprecipitate is usually transfused as a ten unit pool (which contains a volume of about 150 mL).

Red blood cells:

The volume of one unit of packed red blood cells is usually about 300 mL.

If a patient who requires a red blood cell transfusion may not tolerate rapid volume expansion (e.g., a patient with a very low left ventricular ejection fraction), consider transfusing a unit of packed red blood cells in "splits". The unit can be split in two and each of the "splits" can be infused slowly over several hours with intravenous furosemide administered between transfusions. Hyper-packed units that are prepared by removing excess plasma can be requested from the blood bank as well.

In the absence of ongoing bleeding, each unit of packed red blood cells should raise the hemoglobin by 1 g/dL or raise the hematocrit by 3%.

The term "massive blood transfusion" is usually used to signify replacement of more than half the blood volume in 24 hours. Transfusion of large numbers of units of packed red blood cells can cause a dilutional thrombocytopenia or a dilutional coagulopathy. The clinician should begin to monitor serial measurements of PT, aPTT, fibrinogen and platelet count after 5 or more units of red blood cells have been administered. Transfuse with fresh frozen plasma, cryoprecipitate and platelets as needed to keep the PT/aPTT below 1.5 times normal, cryoprecipitate above 100 mg/dL and the platelet count above 50,000/mcL. The citrate used to anticoagulate packed red blood cells can lead to hypocalcemia or metabolic acidosis in patients who receive a very large number of transfused units.

Platelets:

Single donor apheresis platelet units have replaced pooled platelets (four to six random donor platelet concentrates combined into one dose) in many medical centers with the goal of minimizing a recipient's risk of infection and exposure to allogeneic donor exposures.

One unit of single donor apheresis platelets has a volume of 200-500mL.

One unit of single donor apheresis platelets should increase the platelet count by about 60,000/mcL.

Consider transfusing one unit of platelets at a time and recheck platelets prior to ordering additional units; an exception to this would be patients with intracranial bleed and severe thrombocytopenia.

VII. What's the evidence?

Murphy, G J, Pike, K. "Liberal or Restrictive Transfusion after Cardiac Surgery". New England Journal of Medicine. vol. 372. 2015. pp. 997-1008.

(This reference is important to consider when transfusing patients liberally with cardiac disease.)

Goodnough, LT, Brecher, ME, Kanter, MH.

Hebert.

Carson.

Carson.

Carson.

Andreoli, TE, Benjamin, I, Griggs, RC, Wing, EJ. Cecil Essentials of Medicine, 8th Edition. pp. 571-579.

Geiger, TL, Howard, SC. "Acetaminophen and Diphenhydramine Premedication for Allergic and Febrile Non-hemolytic Transfusion Reactions: Good Prophylaxis or Bad Practice". Transfus Med Rev. vol. 21. 2007 January. pp. 1-12.

Hillman, RS. Hematology in Clinical Practice. 2010. pp. 471-472.

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