Abstract
Keywords
Primary Objective
Competency 3: Diagnostic Medicine and Therapeutic Pathology; Topic: (TM) Transfusion medicine; Learning Goal 1: Concepts of Blood Transfusion.
Secondary Objective
Competency 3: Diagnostic Medicine and Therapeutic Pathology; Topic: (TM) Transfusion medicine; Learning Goal 1: Concepts of Blood Transfusion.
Patient Presentation, Part 1
A 25-year-old male presented to his primary care physician with 3 weeks of fatigue and intermittent low-grade fevers. Last year, he recalls being able to run 3 miles easily, but now he becomes short of breath going up a flight of stairs. Otherwise, the patient’s past medical history was unremarkable. A complete blood count (CBC) with differential showed atypical cells consistent with blasts. A bone marrow biopsy was performed along with flow cytometric analysis, confirming a diagnosis of acute lymphoblastic leukemia.
Diagnostic Findings, Part 1
During his admission for induction chemotherapy, he developed high-grade fever (103°F), tachycardia, hypoxia, and hypotension. Otherwise, his physical examination was unremarkable.
Questions/Discussion Points, Part 1
What Is the Differential Diagnosis for Fever in This Patient and What Initial Diagnostic Studies Should Be Performed?
Fever is common in patients with cancer. It can be associated with infectious or noninfectious causes such as chemotherapy, radiation, tumor-associated inflammation, and venous thromboembolism. Since these patients are usually immunocompromised, it is important to initially rule out infection. Complete blood count, blood and urine culture, and chest X-ray were performed.
Diagnostic Findings, Part 2
Chest X-ray was unremarkable. Urine analysis was negative for leukocyte esterase, and no organisms were seen. A urine culture was negative. Complete blood count results are shown in Table 1. Blood culture was positive, and the Gram stain from the blood culture bottle showed gram-negative rods (Figure 1), which were identified as
Complete Blood Counts (CBCs) With Differential.*
Abbreviations: HCT, hematocrit; MCH, mean corpuscular hemogloblin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; RDW, red cell distribution width; WBC, white blood cell.
* The results show pancytopenia with severe neutropenia.
Blood culture isolate gram stain (×100). The Gram stain is positive for gram-negative rods.
Questions/Discussion Points, Part 2
What Is the Clinical Significance of the Patient’s Complete Blood Count Results?
The patient’s CBC shows low hemoglobin (anemia), low platelet (thrombocytopenia), low white blood cells (leukopenia), and severe neutropenia. Leukopenia and in particular neutropenia predispose patients to fungal and bacterial infections. Anemia (hemoglobin <7 g/dL) can lead to tissue hypoxia, altered mental status, and cardiac arrest. Thrombocytopenia increases the chance of bleeding. Patients who are stable and not bleeding can typically tolerate a platelet count above 10/μL. Patients who are bleeding or undergoing invasive procedures are often transfused to maintain a higher platelet count (up to 100/μL for neurosurgical procedures). 2
What Are the Common Types of Blood Products Used for Transfusion?
Common types of blood products are summarized in Table 2. 2 The efficacy of blood product transfusion can be monitored directly (eg, rise in posttransfusion count, coagulation test results) or by assessing efficacy (eg, bleeding assessment, survival).
Blood Products.*,2
* This table shows the common indications, storage conditions, dosing, and methods of monitoring efficacy for the commonly used blood products.
For example, one unit of apheresis platelets should raise the patient’s platelet count by 30 000 to 50 000/μL within 1 hour of transfusion; however, the actual increase will also depend on the recipient blood volume and the platelet content of the unit, among other factors. The platelet count may fail to rise after platelet transfusion either due to antibody-mediated (typically anti-human leukocyte antigen [HLA]) clearance of platelets in circulation, increased consumption of platelets in the setting of clotting, or splenic sequestration as a consequence of splenomegaly. 3
What Are Granulocytes?
Granulocytes are white blood cells, specifically those with prominent intracytoplasmic granules visible by microscopy (neutrophils, eosinophils, and basophils). Neutrophils are the most abundant granulocyte and play an important role in combating bacterial and fungal infections.
Review the Indications for Granulocyte Transfusions
The purpose of granulocyte transfusion is to provide functional neutrophils to combat bacterial or fungal infections. The following are the generally accepted clinical indications of granulocyte transfusion: Neutropenia, absolute neutrophil count <0.5 × 103/μL. Fungal or bacterial infection unresponsive to appropriate therapy for at least 24 to 48 hours. Expectation of neutrophil recovery.
4
Describe Donor Selection for Granulocyte Transfusion
Granulocyte products contain a significant number of red blood cells (RBCs); therefore, they should be ABO/RhD compatible with the recipient and not react with any significant RBC alloantibodies currently or previously detected in the recipient’s plasma. Cytomegalovirus (CMV) seronegative patients should receive granulocytes from CMV seronegative donors.
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Routine donor infectious disease testing takes at least 24 to 48 hours to complete. However, granulocytes begin to lose function within 6 to 8 hours and the product’s shelf life is 24 hours. Therefore, granulocytes must be transfused before the results of donor testing collected at the time of granulocyte donation are available (ie, emergency release).
4,6
Describe Collection Methods and Storage of Granulocyte Product
Like platelets, granulocytes are usually collected by apheresis. Typically, granulocytes are collected after stimulating a donor so that their peripheral blood granulocyte count is increased. Granulocyte-colony stimulating factor yields the highest number of cells per collection; however, steroids are routinely used since they have fewer side effects and are easier to administer (oral vs intravenous). 7 Granulocyte products can be stored at room temperature for up to 24 hours but should be transfused as soon as possible after collection.
Describe the Efficacy and Dose of Granulocyte Transfusion
Randomized control trials studying the efficacy of granulocyte transfusion are difficult to conduct, due to poor enrollment, heterogeneous patient populations with many comorbidities, differences in donor simulation and per kilogram dosing, and the relative infrequency of granulocyte transfusions overall. Studies have suggested greater efficacy with higher numbers of granulocytes per recipient kilogram per dose. Younger recipients with a lower weight may have better outcomes than adult recipients since the per kilogram dose is higher; however, data are limited. 8 -10 An international registry was recently formed to track the use and efficacy of granulocyte transfusions. 11
Diagnostic Findings, Part 3
Three days after the first positive blood culture, the patient remained febrile and was transfused with a granulocyte product. He also received a unit of apheresis collected platelets and a unit of packed RBCs earlier that day. One hour after the granulocyte transfusion, he developed worsening hypoxia requiring intubation. Otherwise, his vital signs and physical examination findings were unremarkable.
Questions/Discussion Points, Part 3
What Is the Differential for This Worsening Hypoxia in the Setting of Transfusion?
Hypoxia is defined as oxygen saturation less than 90% on room air. Symptoms of acute hypoxia during or after the cessation of transfusion should raise concern for a transfusion reaction. Common transfusion reactions are summarized in Table 3. 12,13 Since, this patient had hypoxia prior to transfusion, it might also be due to their underlying medical condition (ie, sepsis in the setting of neutropenia).
Abbreviations: anti-HLA, anti-human leukocyte antigen; IVIG, intravenous immunoglobulin; WBC, white blood cell.
* This table summarizes the commonly recognized transfusion reactions and provides a brief description of their pathophysiology and presentation. The most common prophylaxis and initial management approaches also listed. In the United States, all fatalities that may have been due to transfusion are reportable directly to the US Food and Drug Administration (FDA).
What Are the Common Transfusion Reactions Associated With Granulocyte Transfusion in Particular?
Granulocyte transfusion can cause an increase in cytokines and chemokines and the development of granulocyte-reactive antibodies, which can cause transfusion-related acute lung injury (TRALI). 10,14 Also, granulocyte products contain T-lymphocytes in addition to granulocytes and can cause transfusion-associated graft-versus-host disease (TA-GVHD). Due to the risk of TA-GVHD, all granulocyte products should be irradiated to prevent T-cell duplication in the recipient. 15 Transfusion reactions that are seen with other blood products can also be caused by granulocyte transfusion including febrile nonhemolytic, hemolytic, allergic, and septic reactions in addition to transfusion-associated circulatory overload (TACO).
What Diagnostic Studies Should Be Performed?
If transfusion reaction is suspected, transfusion should be stopped immediately and the blood bank should be notified. The blood bank investigation of a suspected transfusion reaction should include the following:
13,16
Clerical check to confirm correct labeling of the product and patient identification. Visual inspection of the returned blood product bag and tubing. Visual inspection of the recipient’s plasma to look for signs of hemolysis (color change). Repeat ABO Rh typing to confirm previous results. Direct antiglobulin test, also known as the Coombs test, to detect antibodies or complements bound to red blood cells in the patient’s circulation. If a septic reaction is suspected: bacterial culture of residual blood product. If TRALI is suspected: notification of blood supplier and look back to determine whether the blood donor for this product has caused other potential TRALI reactions in the past.
In consultation with the blood bank, clinical evaluation of a suspected transfusion reaction should include the following: Posttransfusion vital signs. To assess for hemolysis: haptoglobin, direct and indirect bilirubin, lactate dehydrogenase (LDH), plasma-free hemoglobin, and urine hemoglobin. If septic reaction is suspected: blood culture drawn from the patient. If respiratory symptoms are present: chest X-ray to assess for pulmonary edema or other causes of respiratory symptoms. If fluid overload is suspected: brain natriuretic peptide (BNP) and the record of fluid balance.
Diagnostic Findings, Part 4
The blood bank investigation revealed no clerical or testing errors, and there was no evidence of hemolysis on visual inspection. Direct antiglobulin test was negative. Chest X-ray showed diffuse bilateral infiltrates. A BNP was elevated (2000 pg/mL, reference range <100 pg/mL), and the chart showed evidence of net positive fluid balance (positive 2 L in the previous 24 hours).
Questions/Discussion Points, Part 4
What Is the Likely Diagnosis for This Patient’s Sudden Hypoxia After Transfusion?
The patient’s reaction could be due to TRALI or TACO. The history of positive net fluid balance and elevated BNP supports a diagnosis of TACO.
How Should This Patient Be Acutely Managed?
Hypoxia associated with TACO should improve with diuresis. In the meantime, oxygen saturation should be maintained with supplemental oxygen as necessary and additional fluid administrated should be minimized.
What Should Be Done Prior to Future Blood Product Transfusions?
Transfusion-associated circulatory overload reactions might be prevented in the future by avoiding fluid overload, diuresis, transfusing slowly, and transfusing volume reduced or split blood products (so that lower volumes are administered). 17
Patient Follow-Up
After receiving 3 daily granulocyte transfusions, the patient became afebrile, showed an increase in neutrophil count, and blood cultures became negative. At this point, granulocyte transfusions were stopped. The patient successfully completed the chemotherapy.
Teaching Points
Granulocyte transfusion is indicated in severe neutropenic patients with bacterial or fungal infection unresponsive to appropriate antimicrobial therapy. Granulocyte transfusion cannot be used indefinitely and should not be used if a patient’s own neutrophil production is not expected to recover. Blood products are life-saving therapeutics that replace whole blood or specific blood components (eg, platelets, RBCs, coagulation factors). All blood products are associated with transfusion reactions that can mimic a patient’s underlying medical condition. Prompt recognition and investigation of a possible transfusion reaction is essential for acute management and future prophylaxis.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.