Blood Transfusion in Patients Having Hematologic Malignancies and Solid Tumors: Problems Associated with AIHA and Unidentifiable RBC Alloantibodies
By Aida Narvios and Benjamin Lichtiger
Copyright 1993-2010 The University of Texas MD Anderson Cancer Center, Houston, Texas. All rights reserved.
In patients who present with autoimmune hemolytic anemia (AIHA), which is defined as survival of shortened red blood cells (RBCs) due to a humoral immune response (1) along with a positive direct antiglobulin test (DAT), unidentifiable RBC alloantibodies and possibly RBC autoantibodies pose significant challenges to members of any transfusion service in their quest to find compatible blood units for transfusion. Transfusion therapy in such patients can be hazardous and lead to serious deleterious effects, as specific clinically significant hemolytic RBC alloantibodies may be missed or masked by the nonspecific antibodies associated with AIHA.
AIHA is caused by the presence of nonspecific and identifiable antibodies that react with the surface antigenic moieties of RBCs. When the rate of RBC destruction exceeds the regenerative capacity of the bone marrow, anemia results. In autoimmune hemolysis, however, the coating of autoantibodies does not damage the RBCs but does cause hemolysis by activating complements, inducing interactions with effector cells mainly in the mononuclear phagocyte system, or both. (2-6). The nature of the clinical evolution of AIHA and the treatment modalities for its associated pathologies make it necessary to provide the patient with blood transfusions.
AIHA is an unusual complication of malignancy. Its true incidence is difficult to assess, because subthreshold quantities of immunoglobulin in RBCs may remain undetected without the use of special techniques (8). Also, isoimmunization after transfusion can obscure the diagnosis of AIHA (9). Patients having lymphocytic malignancies, mostly those of the B-cell type, account for almost half of all cases of secondary AIHA (10,11). In particular, chronic lymphocytic leukemia and lymphomas are the malignancies most often accompanied by warm-type AIHA; about 25.0% of chronic lymphocytic leukemia patients, 2.0%-3.0% of non-Hodgkin's lymphoma patients (13), and 2.3% of Hodgkin's disease patients exhibit AIHA (14). Patients having solid tumors, especially carcinomas and ovarian tumors, may also suffer from AIHA. Indeed, about 30 patients having both ovarian germ cell tumors and AIHA have been reported (15). Occasionally, Coombs'-positive anemia is even seen in patients having solid tumors of the breast, lung, colon, pancreas, testis, kidney, thymus, and uterus (9,16-23).
Unfortunately, the process of identifying clinically effective transfusable RBC units is lengthy, labor intensive, complicated, and expensive. Usually, the best that a transfusion service can do is identify and offer units of RBCs that are barely incompatible with the patient's blood, even though such "least incompatible" units may not survive in the circulation if a clinically significant hemolytic antibody is present. The aim, however, is to give the patient blood that is compatible with his or her blood group, except for in those rare instances when the patient's autoantibodies are A or B antigen-specific and he or she is given group O blood instead (7).
In the present study, we retrospectively reviewed our experience with 14 patients who had AIHA in association with a variety of neoplastic diseases. We found that even though all 14 patients had received least incompatible RBC transfusions almost exclusively, none of them had any evidence of hemolysis or other untoward effects. In addition, we found that the RBC transfusions did not prevent sustained elevated hemoglobin levels afterward.
Materials and Methods
The medical and transfusion service records of 14 patients seen at The University of Texas MD Anderson Cancer Center from January 1994 to December 1999 who had overtly detectable autoantibodies against RBCs and immunohematologic evidence of AIHA were examined retrospectively. Eleven of the patients were male, while three were female; they ranged in age from 8 to 81 years, and they were seen for a variety of diseases.
The inclusion criteria were a positive DAT, a positive reaction with all antibody panel cells tested, and receipt of at least one incompatible blood transfusion. All 14 patients met these criteria.
The transfusion parameters analyzed were the pretransfusion and posttransfusion levels of hemoglobin, total bilirubin, and lactate dehydrogenase (LDH). The patients' clinical records had no information on spleen size or haptoglobin or hemosiderin level in the urine. However, their laboratory records showed that each patient had autoantibodies and that the presence of underlying alloantibodies could not be entirely ruled out.
Finally, data were analyzed in terms of the effect (increment, decrement, or no change) on hemoglobin, bilirubin, and LDH levels produced by each transfused unit.
All of the patients in this study had underlying malignancies. Their hemoglobin levels prior to transfusion therapy ranged from 2.8 to 8.7 g/dl. After transfusion, their levels ranged from 7.1 to 11.7 g/dl. Two patients received both compatible and least incompatible blood units. The hemoglobin-level increases seen in these patients after transfusion of the least incompatible units were similar to those seen after transfusion of compatible units (Table 1).
Table 1. Transfusion Effects on Hemoglobin Levels*
|Diagnosis||No. of patients showing an Hgb increase||No. of least incompatible units transfused||Average Hgb increase per unit, g/dl (range, 0.2-2.1)|
Leukemia (CLL, CML, or ALL)/mL)
*Hgb, hemoglobin; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphocytic leukemia.
In addition, two patients showed Rh specificity for anti-e antibodies. One of these patients received an anti-e--negative, crossmatched compatible unit and a least incompatible unit of packed red blood cells (PRBCs). As a result, that patient's hemoglobin level rose from 8.0 to 8.9 g/dl after transfusion of the compatible unit and from 7.5 to 9.6 g/dl after transfusion of the least incompatible unit. Additionally, the second patient received 4 units of least incompatible PRBCs. As a result, that patient had a pretransfusion hemoglobin level of 5.9 g/dl and a posttransfusion level of 9.3 g/dl.
Eight transfusions in our study resulted in a positive reaction to complements as shown by the DAT results. In contrast, seven transfusions resulted in a negative reaction. The average increase in hemoglobin level was 0.99 g/dl per least incompatible unit transfused in the positive cases versus 0.93 g/dl per least compatible unit transfused in the negative ones. Furthermore, seven patients had an increase in total bilirubin level (Table 2). Their increases ranged from 0.02 to 0.45 mg/dl (mean, 0.11 mg/dl per unit). Also, six patients had an increase in LDH level (mean, 40.39 IU/dl).
Table 2. Transfusion Effects on Bilirubin and LDH Level
No. of patients showing an increase
No. of least incompatible units transfused
Average increase per unit
Patients who suffer from hematologic or other malignancies associated with AIHA and have a positive DAT score have a heightened risk of hemolysis with blood transfusions. This is due to the presence of unidentifiable RBC alloantibodies, including autoantibodies having strong hemolytic potential, that make the selection of transfusable units of blood highly complex and risky in terms of patient outcome. Interestingly, in the 14 cases reported herein, transfusion of least incompatible PRBCs was not followed by the appearance of significant laboratory or clinical symptoms or signs of hemolysis. In fact, the 14 patients had an average increase in hemoglobin level of 0.99 g/dl per unit transfused.
Of the two patients who had anti-e antibodies identified in their serum, one received a transfusion of a compatible anti-e--negative blood unit, while the other received least incompatible units. Yet again, no significant differences in hemoglobin-level increments were noted. Furthermore, all of the patients whose DAT results were positive for complements had an increase in hemoglobin level of 0.99 g/dl per unit, which was slightly higher than the increase seen in patients whose DAT results were negative for complements. The results of laboratory work-up for signs of hemolysis, such as changes in the LDH and bilirubin level, were not significant enough to explain obvious hemolysis; unfortunately, the patients' haptoglobin levels were not available.
In our review, we observed uncontrollable factors that had a minimal impact on our final results, such as weight, fluid intake, blood volume, current disease state, in vitro hemolysis, and chemotherapy effects. Nevertheless, the results and information we obtained suggest that transfusing least incompatible units to decompensated AIHA patients should not be ruled out unconditionally. Specifically, our results support those of Salama et al. (15), who reported the absence of a definite increase in hemolysis in 53 patients who received blood transfusions for decompensated AIHA, even when the transfused RBCs were serologically incompatible because of the presence of free serum autoantibodies. Our results also concur with those of Salama and colleagues in suggesting that adverse hemolytic transfusion reactions are less common in AIHA patients.
If blood transfusion is indeed reasonably safe in AIHA patients, then it will obviously have benefits in terms of technologist time spent on the procedure, reagent cost, and ultimately, the cost to the patient and thus blood availability. Nonetheless, in patients having severe AIHA, RBCs must still be transfused cautiously and for appropriate indications. Furthermore, good communication with the patient's primary care team and caregivers is highly recommended. Such communication may lead to recommendations of tests of the haptoglobin level as well as routine tests of the hemosiderin level in urine in all cases in which a transfusion service identifies AIHA. Although these additional tests may slightly increase the cost of clinical care and management, the information provided by them may justify the appropriateness of our strategy of releasing least incompatible blood for transfusion and assessing the clinical outcome.
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