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Plasma exchange in the management of delayed hemolytic transfusion reaction
Trunsfus. Sci. 1990; 11:91-96
09553886/90
$3.00+0.00
Copyright 0 1990 Pergamon Press plc
Printed in Great Britain. All rights reserved
Plasma’ Exchange in the Management of Delayed Hemolytic Transfusion Reaction Rhonda D. Wright, MD P. Joyce Larison, MT(ASCP)SBB Lloyd 0. Cook, MD
n Two patients are described who developed delayed hemolytic transfusion reactions due to anti-Jk”. The use of plasma exchange in these patients expedited their recovery by reducing the burden of hemolysis and by removing circulating anti- Jka antibodies. The decision to employ plasma exchange must be based on a consideration of the clinical status of individual patient the involved. n
describe the outcome approach.
of this therapeutic
CASE HISTORY
1
A 26-yr-old nulliparous black female with no significant past medical history was admitted to an outside hospital because of severe anemia (hematocrit 12.4% ) though to be secondary to heavy vaginal bleeding beginning 4 days earlier after discontinuing oral contraceptives. Laboratory tests, however, showed evidence of severe hemolysis (see Table 1J. She was given two units of packed red blood cells (RBCs) on the day of admission and three more units the next day. 5 days later she was transferred to the Medical College of Georgia Hospital (MCGH) for further evaluation. Upon arrival, in addition to the laboratory values shown in Table 1, the patient’s direct antiglobulin test (DAT) was weakly positive, although her antibody screen was negative. Her reticulocyte index was 24.9% and her platelet count was 30,000/mm.3 Her provisional diagnosis was autoimmune hemolytic anemia and idiopathic thrombocytopenit purpura, which were thought to be manifestations of an emerging autoimmune disease such as systemic lupus erythematosus (SLE). The patient stated that she was allergic to sulfa drugs, but also admitted to taking Lasix@ (furosemide) as a diuretic for weight loss. 3 days after admission, she was begun on 60 mg of prednisone daily, but hemolysis con-
INTRODUCTION Delayed hemolytic transfusion reaction (DHTR) is an antibody-mediated phenomenon involving the destruction of homologous erythrocytes by an immune response which does not become manifest until between 2 and 21 days following transfusion. Although generally much less severe than immediate hemolytic reactions, DHTRs can cause significant morbidity, and are an oftenoverlooked complication of transfusion therapy.’ Severe cases do not always respond to current treatment modalities, and several deaths due to DHTR have been reported.2-5 In the last 7 yr, 2 patients with severe DHTRs seen in our institution have been treated with plasma exchange. The following reports of Pathology, Medical allege of Georgia, Augusta, Georgia, U.S.A. Received 8/89; Accepted WS9.
Fromthe BloodBank,Department
91
92
Transfus. Sci.
Table 1.
Vol. 11, No. 1
Laboratory Values, Case 1
Date
Hct (%)
612
12.4
Total BiIirubin (mg/a) 5.2
Indirect ‘;“ir$ii m 4.1
LDH (mu/n&) 1538
Haptoglobin (m&W l
Urine Hemoglobin
Negative
ki8 Transfused 21.5 5 units 1.3 RBCs 6/2-6/4 0.5 6114 12.7 3.4 2.2
1600 2052
~0.8 l
l
6ji6Transfused 15.1 3 units 2.3 IU3Cs 6114 2.1 6117 13.2 2.8 (a-;RBCs
t 3690
t t
Large
6/181420 549
t t
Moderate Negative
6ji9Plasma 25.4 exchange + 1.1 2 units Jk 6124 33.5 0.6
0.7 l
Negative
l
‘Not performed. tinued, and she began to pass large amounts of free hemoglobin in her urine. She also became febrile to >39.o”C. New samples of blood sent to the Blood Bank began to show weak positivity in the indirect antiglobulin phase of the antibody screen, and preliminary studies indicated that she might be developing antibodies to E and Lea antigens. Accordingly, the three units of crossmatchcompatible RBCs with which she was transfused 3 days later were E- and Le (a-). Meanwhile, blood was sent to the Atlanta branch of the American Red Cross for evaluation, and they determined that the patient had anti-Jka and possibly anti-E rather than anti-Lea. Subsequent investigation showed that all eight units the patient had already received at MCGH and at the referring hospital were Jk (a+). Because of continuing hemolysis in the face of prednisone therapy, a 3-L plasma exchange was performed 4 days after the last Jk (a+) transfusion. The replacement solution for this procedure was 5% albumin. The patient also received two more units of RBCs that were Jk (a-). Improvement thereafter was rapid, with hematocrit rising to 33.5% and platelets to 530,000/mm3 at time of discharge 6 days later. Additionally, lactate dehydrogenase (LDH) had decreased to 549 mU/mL and total bilirubin to 0.6 mg/dL, and urine hemoglobin was not detectable. The patient continued to do well.
Tests for antinuclear antibody and rheumatoid factor were repeatedly negative, and she was easily tapered off corticosteroids. Her vaginal bleeding resolved with hormonal therapy, and there have been no subsequent episodes of anemia or hemolysis. CASE HISTORY 2 A 55-yr-old multiparous white female with severe atherosclerotic peripheral vascular disease secondary to hypercholesterolemia and heavy smoking had had several vascular procedures at other hospitals requiring multiple transfusions in the past. During pre-operative evaluation for a revision of her aortobifemoral Y-graft, an antibody panel showed anti-V and a cold autoagglutinin as well as a weakly positive antiglobulin-phase reaction that did not conclusively fit another antibody pattern. Her DAT was positive with polyspecific anti-human globulin and with anti-IgG. Elution showed only a panagglutinin. Eight units of cross crossmatch-compatible blood were made available with a stipulation that she must be transfused with caution and kept warm during transfusion. She was admitted to MCGH and had surgery on the following day, during which she received three units of RBCs. Four additional units were transfused over the next 6 days. Surgery was without complications, but the patient had a very difficult post-
PE in the Management
of DHTR 93
Table 2. Laboratory Values, Case 2 Date
Hct W)
TotaI
Indirect
0.5 0.4 lo/18 35.0 Transfused 7 units RBCs 10/18-lo/24 4.5 0.1 ibj24 29.3 8.7 3.0 10127 24.5 11.6 21.0 4.8 lo/28 Plasma exchange lo/28 8.6 3.3 i&30 25.4 6.7 2.0 27.2 11/7 4.6 1.7 11/29 28.7 1.2 0.1 31.6 12/18
LDH
154 767 1074 487 800 720 515 305
Haptoglobin (m&W
Urine Hemoglobin
+ l
l
Negative Negative Negative Negative Negative Negative Negative Negative
*Not performed. operative course due to chronic obstructive pulmonary disease, which resulted in the development of pneumonia and adult respiratory distress syndrome. 6 days after surgery, the patient began to have a decreasing hematocrit and increasing bilirubin and LDH [see Table 2) which were not adequately explained by her respiratory and infectious complications. Hematology-Oncology Service was consulted and a diagnosis of combined warm and cold autoimmune hemolytic anemia was made, for which the consultants recommended plasma exchange and corticosteroids. Accordingly, a 3L plasma exchange was performed 10 days after surgery. The replacement solution for this procedure was 5% albumin. A blood sample drawn the previous day, however, clearly demonstrated for the first time that the patient had antibody to Jk”. On further investigation, only one of the seven units of RBCs transfused to this patient was shown to be Jk a[ -), and it seemed most likely that the patient’s hemolysis was in fact due to a delayed hemolytic transfusion reaction secondary to Jk [a+) blood. Following plasma exchange, the patient’s laboratory values slowly improved, and it became possible to begin to taper her corticosteroid dose only 4 days after the procedure. She continued to have a difficult, prolonged recovery due to pulmonary and infectious complications and required numer-
ous further transfusions of Jk (a-) RBCs, but hemolysis did not recur. She was finally discharged 4 months after surgery, and is back to her usual state of health as of this writing. DISCUSSION Delayed hemolytic transfusion reaction is an insidious and frequently unrecognized complication of RBC transfusion. Its reported incidence ranges from 1:220776 to 1 :50007 units transfused, the great differences in reported frequency due at least in part to differences in the sensitivity of the methods used to discover subclinical cases of DHTR.8 It is usually caused by an anamnestic (secondary) response to RBC antigens to which the patient has previously been sensitized by transfusion or by pregnancy with subsequent decline of the antibody titer to a level undetectable by routine testing methods,9 although in rare cases the reaction appears to be due to a rapidly evolving primary sensitization to one or more RBC units only recently transfused.6,10 In either instance, the pretransfusion screen for unexpected antibodies will have been negative. In other cases, the antibody screen was equivocal, and attempts to determine antibody specificity failed or were incomplete at the time the patient was transfused (as happened in our second case). The RRC units involved will have appeared to be compatible by crossmatch, but their infusion will be followed by a decrease in hemog-
94
Tzansfus. Sci.
Vol. 11. No. 1
lobin and hematocrit values rather than the expected increase, and previouslyunidentified RBC alloantibodies will begin to appear in post-transfusion blood samples. Other signs of hemolysis, such as positive direct and indirect antiglobulin tests, increasing levels of serum LDH and unconjugated bilirubin, and decreasing serum haptoglobin, can be documented in most cases. More severe cases may also show hemoglobin in urine and plasma. The most common clinical sign is fever, sometimes accompanied by chills or backache. The length of time between transfusion and appearance of a DHTR depends in part on whether the original sensitization occurred during an earlier transfusion or pregnancy, in which case the interval may be as little as 2 days,3 or whether sensitization occurred during a recent transfusion, with the response evolving rapidly enough to cause hemolysis of the still-circulating transfused RBCs. In the latter case, the reaction may take as little as 9 days’ or as long as 4 weekslo to develop. Many antibodies have been reported to cause DHTR, but antibodies to Kidd antigens, especially anti- Jka, are implicated most often.3*718These antibodies often sink to undetectable levels shortly after the sensitizing event, only to rebound quickly and with notable hemolytic effect upon re-exposure to the eliciting Kidd antigen. 7-9 They also tend to show dosage,9 that is, serum reactions against panel cells heterozygous for Kidd antigens tend to be much weaker than reactions to homozygous cells; therefore antibodies to Kidd antigens may be mistaken for antibodies of other specificities on the initial identification panel. A further complication is the existence of more than one alloantibody specificity in many patients with DI-ITR.‘fS Because of the difficulties of discovering and defining Kidd and other antibodies resulting from sensitizing events occurring in a patient’s distant medical history, careful review of old transfusion histories and avoidance of unnecessary transfusion are the most useful currently available methods of attempting to avoid
complication of transfusion therapy, lr3 -although more sensitive crossmatch techniques might prevent some cases.3,s DHTR is frequently misdiagnosed and its hemolysis attributed to some other cause, as happened initially in both of the cases we report. In particular, a mistaken diagnosis of autoimmune hemolytic anemia may be made, especially when DHTR is accompanied by the appearance of multiple antibody specificities.‘*6F11However, in DHTR, the DAT and the autocontrol are typically only weakly and transiently positive,‘t3 and examination of the peripheral smear will show fewer spherocytes and schistocytes than expected in autoimmune hemolysis.li Plasma exchange was performed in both of the reported patients because they were thought to have autoimmune hemolytic anemia, and the complexity of both of these cases illustrates the difficulty of avoiding this diagnostic pitfall. Restrospectively, it seems likely that the first patient’s anemia, which was hemolytic in nature at the time of presentation, was initially caused by the use of furosemide in a sulfonamide-sensitive patient. This reaction frequently mimics autoimmune disease, notably SLE. Examination of her laboratory data shows that she responded to the first set of transfusions with a rise in hematocrit, and her hemolysis seemed to be resolving. (She was no longer taking furosemide.) Approximately 9 days later, she entered a second phase of illness with a rapidly declining hematocrit and rising indirect bilirubin. She was given three more units of Jk(a+) RBCs, and 2 days after this antigenic challenge she was in florid hemolysis. Her response to plasma exchange was equally dramatic, with a substantial decline in bilirubin, LDH, and urine hemoglobin by the following day, and with prompt improvement in her hematocrit. We have been unable to elicit any history of prior transfusion or pregnancy in this patient, and her case appears to be one of rapid sensitization due in part to administration of large this
PE in the Management of DHTR
quantities (8 units) of antigen-positive RBCs over a short period of time ( 12 days). The second patient, who had a much more rapid development of DHTR (6 days), is more typical of DHTR patients in that she is both multiparous and multiply-transfused. Her response to plasma exchange was not as dramatic as that of the first patient, probably because of her underlying poor state of health [which included non-A, non-B hepatitis with mild liver dysfunction exacerbated by hypoxia), but the therapy ultimately appears to have reversed the hemolytic episode. Most cases of DHTR are very mild, some consisting only of laboratory evidence of transient hemolysis, as outlined above. On the other hand, some cases are more severe, and several deaths due primarily or partially to DHTR have been reported. 2-5 The life-threatening consequences of DHTR are attributable to excessive hemolysis and include hypotension, renal failure, and disseminated intravascular coagulation (DIC). Current treatment of severe DHTR is similar to that of immediate hemolytic transfusion reaction, and includes administration of mannitol and/or furosemide to aid renal function and heparin to prevent or reverse DIC. To our knowledge, plasma exchange has not been reported previously as a therapeutic modality for severe DHTR, but we believe that our cases demonstrate its efficacy. We believe that plasma removal and replacement is beneficial to these patients because it effects the immediate removal of significant quantities of two harmful substances: the products of hemolysis, notably free hemoglobin, and the circulating anti-RBC antibodies which cause continued hemolysis. Most cases of DHTR will resolve with more conservative management, however, and we recommend that this therapeutic approach be reserved for patients who fail to respond to such management and who remain at risk for significant morbidity or mortality. In our opinion, the identification of such patients is less a matter of specific numerical values than of TS11:1-G
95
clinical evidence that the patient’s ability to tolerate and resolve the DHTR is impaired. We suggest that the following parameters be considered in assessing the need for plasma exchange in a DHTR patient: ill Evidence of overwhelming hemolysis, as discussed above: increase in serum (a) marked indirect bilirubin and LDH; (b) decrease in serum haptoglobin; (c) presence of free hemoglobin in plasma or urine. 12)Severe anemia, e.g. hemoglobin < 7.0 mg/dL or hematocrit < 21%. (3) Evidence of inability to tolerate impairment of oxygen-carrying capacity, such as: (a) decrease in PO,; (b) dyspnea: (c) obtundation or other change in neurologic status: (d) electrocardiographic changes, such as tachycardia or arrhythmia. (4) Evidence of DIC: purpura, mucosal bleeding, increase in fibrin degradation products, decrease in platelet count, etc. (5) Hypotension. In summary, we believe that plasma exchange is helpful in the treatment of severe DHTR because of its ability to effect rapid removal of deleterious products of hemolysis. The decision to employ plasma exchange must be based on an evaluation of the degree to which DHTR is contributing to morbidity in the individual patient involved. REFERENCES 1. Solanki D, McCurdy PR: Delayed hemo-
lytic transfusion reactions: an oftenmissed entity. I Am Med Assoc 1978;
239:729-731. 2. Bove JR: Delayed complications of transfusion. Conn Med 1968; 32~36. 3. Pineda AA, Taswell HF, Brzica SM, Jr: Delayed hemolytic transfusion reaction: an immunologic hazard of blood transfusion. Transfusion 1978; 18:1-7. 4. Hillman NM: Fatal delayed hemolytic transfusion reaction due to antioc + E. Transfusion 1979; 19548551.
96
Transfus. Sci. Vol. 11, No. 1 Schorn TF, Knospe WH: Fatal delayed hemolytic transfusion reaction without previous blood transfusion. Ann Intern Med 1989; 110:241-242. Croucher BEE, Crookston MC, Crookston JH: Delayed haemolytic transfusion reactions simulating autoimmune haemolytic anemia. VOX Sang 1967; 12:32. Taswell HF, Pineda AA, Moore SB: Hemolytic transfusion reactions: frequency and clinical and laboratory aspects, in Bell CA (ed): A Seminar on Immune-Mediated Cell Destruction. Chicago, American Association of Blood Banks, 1981, pp. 71-92. Moore SB, Taswell HF, Pineda AA, Son-
nenberg CL: Delayed hemolytic transfusion reactions: evidence of the need for an improved pretransfusion compatibility test. Am 1 Clin Path01 1980; 74~94-97. 9. Mollison PL, Engelfreit CP, Contreras M: Blood Transfusion in Clinical Medicine, 8th Edn. Oxford, Blackwell, 1987, pp. 381382 and 617-630. 10. Patten E, Reddi CR, Riglin H, Edwards J: Delayed hemolytic transfusion reaction caused by a primary immune response. Transfusion 1982; 22:248-250. 11 Rothman IK, Alter HJ, Strewler GJ: Delayed over hemolytic transfusion reaction due to to anti-U antibody. Transfusion 1976; 16: 357360.
09553886/90
$3.00+0.00
Copyright 0 1990 Pergamon Press plc
Printed in Great Britain. All rights reserved
Plasma’ Exchange in the Management of Delayed Hemolytic Transfusion Reaction Rhonda D. Wright, MD P. Joyce Larison, MT(ASCP)SBB Lloyd 0. Cook, MD
n Two patients are described who developed delayed hemolytic transfusion reactions due to anti-Jk”. The use of plasma exchange in these patients expedited their recovery by reducing the burden of hemolysis and by removing circulating anti- Jka antibodies. The decision to employ plasma exchange must be based on a consideration of the clinical status of individual patient the involved. n
describe the outcome approach.
of this therapeutic
CASE HISTORY
1
A 26-yr-old nulliparous black female with no significant past medical history was admitted to an outside hospital because of severe anemia (hematocrit 12.4% ) though to be secondary to heavy vaginal bleeding beginning 4 days earlier after discontinuing oral contraceptives. Laboratory tests, however, showed evidence of severe hemolysis (see Table 1J. She was given two units of packed red blood cells (RBCs) on the day of admission and three more units the next day. 5 days later she was transferred to the Medical College of Georgia Hospital (MCGH) for further evaluation. Upon arrival, in addition to the laboratory values shown in Table 1, the patient’s direct antiglobulin test (DAT) was weakly positive, although her antibody screen was negative. Her reticulocyte index was 24.9% and her platelet count was 30,000/mm.3 Her provisional diagnosis was autoimmune hemolytic anemia and idiopathic thrombocytopenit purpura, which were thought to be manifestations of an emerging autoimmune disease such as systemic lupus erythematosus (SLE). The patient stated that she was allergic to sulfa drugs, but also admitted to taking Lasix@ (furosemide) as a diuretic for weight loss. 3 days after admission, she was begun on 60 mg of prednisone daily, but hemolysis con-
INTRODUCTION Delayed hemolytic transfusion reaction (DHTR) is an antibody-mediated phenomenon involving the destruction of homologous erythrocytes by an immune response which does not become manifest until between 2 and 21 days following transfusion. Although generally much less severe than immediate hemolytic reactions, DHTRs can cause significant morbidity, and are an oftenoverlooked complication of transfusion therapy.’ Severe cases do not always respond to current treatment modalities, and several deaths due to DHTR have been reported.2-5 In the last 7 yr, 2 patients with severe DHTRs seen in our institution have been treated with plasma exchange. The following reports of Pathology, Medical allege of Georgia, Augusta, Georgia, U.S.A. Received 8/89; Accepted WS9.
Fromthe BloodBank,Department
91
92
Transfus. Sci.
Table 1.
Vol. 11, No. 1
Laboratory Values, Case 1
Date
Hct (%)
612
12.4
Total BiIirubin (mg/a) 5.2
Indirect ‘;“ir$ii m 4.1
LDH (mu/n&) 1538
Haptoglobin (m&W l
Urine Hemoglobin
Negative
ki8 Transfused 21.5 5 units 1.3 RBCs 6/2-6/4 0.5 6114 12.7 3.4 2.2
1600 2052
~0.8 l
l
6ji6Transfused 15.1 3 units 2.3 IU3Cs 6114 2.1 6117 13.2 2.8 (a-;RBCs
t 3690
t t
Large
6/181420 549
t t
Moderate Negative
6ji9Plasma 25.4 exchange + 1.1 2 units Jk 6124 33.5 0.6
0.7 l
Negative
l
‘Not performed. tinued, and she began to pass large amounts of free hemoglobin in her urine. She also became febrile to >39.o”C. New samples of blood sent to the Blood Bank began to show weak positivity in the indirect antiglobulin phase of the antibody screen, and preliminary studies indicated that she might be developing antibodies to E and Lea antigens. Accordingly, the three units of crossmatchcompatible RBCs with which she was transfused 3 days later were E- and Le (a-). Meanwhile, blood was sent to the Atlanta branch of the American Red Cross for evaluation, and they determined that the patient had anti-Jka and possibly anti-E rather than anti-Lea. Subsequent investigation showed that all eight units the patient had already received at MCGH and at the referring hospital were Jk (a+). Because of continuing hemolysis in the face of prednisone therapy, a 3-L plasma exchange was performed 4 days after the last Jk (a+) transfusion. The replacement solution for this procedure was 5% albumin. The patient also received two more units of RBCs that were Jk (a-). Improvement thereafter was rapid, with hematocrit rising to 33.5% and platelets to 530,000/mm3 at time of discharge 6 days later. Additionally, lactate dehydrogenase (LDH) had decreased to 549 mU/mL and total bilirubin to 0.6 mg/dL, and urine hemoglobin was not detectable. The patient continued to do well.
Tests for antinuclear antibody and rheumatoid factor were repeatedly negative, and she was easily tapered off corticosteroids. Her vaginal bleeding resolved with hormonal therapy, and there have been no subsequent episodes of anemia or hemolysis. CASE HISTORY 2 A 55-yr-old multiparous white female with severe atherosclerotic peripheral vascular disease secondary to hypercholesterolemia and heavy smoking had had several vascular procedures at other hospitals requiring multiple transfusions in the past. During pre-operative evaluation for a revision of her aortobifemoral Y-graft, an antibody panel showed anti-V and a cold autoagglutinin as well as a weakly positive antiglobulin-phase reaction that did not conclusively fit another antibody pattern. Her DAT was positive with polyspecific anti-human globulin and with anti-IgG. Elution showed only a panagglutinin. Eight units of cross crossmatch-compatible blood were made available with a stipulation that she must be transfused with caution and kept warm during transfusion. She was admitted to MCGH and had surgery on the following day, during which she received three units of RBCs. Four additional units were transfused over the next 6 days. Surgery was without complications, but the patient had a very difficult post-
PE in the Management
of DHTR 93
Table 2. Laboratory Values, Case 2 Date
Hct W)
TotaI
Indirect
0.5 0.4 lo/18 35.0 Transfused 7 units RBCs 10/18-lo/24 4.5 0.1 ibj24 29.3 8.7 3.0 10127 24.5 11.6 21.0 4.8 lo/28 Plasma exchange lo/28 8.6 3.3 i&30 25.4 6.7 2.0 27.2 11/7 4.6 1.7 11/29 28.7 1.2 0.1 31.6 12/18
LDH
154 767 1074 487 800 720 515 305
Haptoglobin (m&W
Urine Hemoglobin
+ l
l
Negative Negative Negative Negative Negative Negative Negative Negative
*Not performed. operative course due to chronic obstructive pulmonary disease, which resulted in the development of pneumonia and adult respiratory distress syndrome. 6 days after surgery, the patient began to have a decreasing hematocrit and increasing bilirubin and LDH [see Table 2) which were not adequately explained by her respiratory and infectious complications. Hematology-Oncology Service was consulted and a diagnosis of combined warm and cold autoimmune hemolytic anemia was made, for which the consultants recommended plasma exchange and corticosteroids. Accordingly, a 3L plasma exchange was performed 10 days after surgery. The replacement solution for this procedure was 5% albumin. A blood sample drawn the previous day, however, clearly demonstrated for the first time that the patient had antibody to Jk”. On further investigation, only one of the seven units of RBCs transfused to this patient was shown to be Jk a[ -), and it seemed most likely that the patient’s hemolysis was in fact due to a delayed hemolytic transfusion reaction secondary to Jk [a+) blood. Following plasma exchange, the patient’s laboratory values slowly improved, and it became possible to begin to taper her corticosteroid dose only 4 days after the procedure. She continued to have a difficult, prolonged recovery due to pulmonary and infectious complications and required numer-
ous further transfusions of Jk (a-) RBCs, but hemolysis did not recur. She was finally discharged 4 months after surgery, and is back to her usual state of health as of this writing. DISCUSSION Delayed hemolytic transfusion reaction is an insidious and frequently unrecognized complication of RBC transfusion. Its reported incidence ranges from 1:220776 to 1 :50007 units transfused, the great differences in reported frequency due at least in part to differences in the sensitivity of the methods used to discover subclinical cases of DHTR.8 It is usually caused by an anamnestic (secondary) response to RBC antigens to which the patient has previously been sensitized by transfusion or by pregnancy with subsequent decline of the antibody titer to a level undetectable by routine testing methods,9 although in rare cases the reaction appears to be due to a rapidly evolving primary sensitization to one or more RBC units only recently transfused.6,10 In either instance, the pretransfusion screen for unexpected antibodies will have been negative. In other cases, the antibody screen was equivocal, and attempts to determine antibody specificity failed or were incomplete at the time the patient was transfused (as happened in our second case). The RRC units involved will have appeared to be compatible by crossmatch, but their infusion will be followed by a decrease in hemog-
94
Tzansfus. Sci.
Vol. 11. No. 1
lobin and hematocrit values rather than the expected increase, and previouslyunidentified RBC alloantibodies will begin to appear in post-transfusion blood samples. Other signs of hemolysis, such as positive direct and indirect antiglobulin tests, increasing levels of serum LDH and unconjugated bilirubin, and decreasing serum haptoglobin, can be documented in most cases. More severe cases may also show hemoglobin in urine and plasma. The most common clinical sign is fever, sometimes accompanied by chills or backache. The length of time between transfusion and appearance of a DHTR depends in part on whether the original sensitization occurred during an earlier transfusion or pregnancy, in which case the interval may be as little as 2 days,3 or whether sensitization occurred during a recent transfusion, with the response evolving rapidly enough to cause hemolysis of the still-circulating transfused RBCs. In the latter case, the reaction may take as little as 9 days’ or as long as 4 weekslo to develop. Many antibodies have been reported to cause DHTR, but antibodies to Kidd antigens, especially anti- Jka, are implicated most often.3*718These antibodies often sink to undetectable levels shortly after the sensitizing event, only to rebound quickly and with notable hemolytic effect upon re-exposure to the eliciting Kidd antigen. 7-9 They also tend to show dosage,9 that is, serum reactions against panel cells heterozygous for Kidd antigens tend to be much weaker than reactions to homozygous cells; therefore antibodies to Kidd antigens may be mistaken for antibodies of other specificities on the initial identification panel. A further complication is the existence of more than one alloantibody specificity in many patients with DI-ITR.‘fS Because of the difficulties of discovering and defining Kidd and other antibodies resulting from sensitizing events occurring in a patient’s distant medical history, careful review of old transfusion histories and avoidance of unnecessary transfusion are the most useful currently available methods of attempting to avoid
complication of transfusion therapy, lr3 -although more sensitive crossmatch techniques might prevent some cases.3,s DHTR is frequently misdiagnosed and its hemolysis attributed to some other cause, as happened initially in both of the cases we report. In particular, a mistaken diagnosis of autoimmune hemolytic anemia may be made, especially when DHTR is accompanied by the appearance of multiple antibody specificities.‘*6F11However, in DHTR, the DAT and the autocontrol are typically only weakly and transiently positive,‘t3 and examination of the peripheral smear will show fewer spherocytes and schistocytes than expected in autoimmune hemolysis.li Plasma exchange was performed in both of the reported patients because they were thought to have autoimmune hemolytic anemia, and the complexity of both of these cases illustrates the difficulty of avoiding this diagnostic pitfall. Restrospectively, it seems likely that the first patient’s anemia, which was hemolytic in nature at the time of presentation, was initially caused by the use of furosemide in a sulfonamide-sensitive patient. This reaction frequently mimics autoimmune disease, notably SLE. Examination of her laboratory data shows that she responded to the first set of transfusions with a rise in hematocrit, and her hemolysis seemed to be resolving. (She was no longer taking furosemide.) Approximately 9 days later, she entered a second phase of illness with a rapidly declining hematocrit and rising indirect bilirubin. She was given three more units of Jk(a+) RBCs, and 2 days after this antigenic challenge she was in florid hemolysis. Her response to plasma exchange was equally dramatic, with a substantial decline in bilirubin, LDH, and urine hemoglobin by the following day, and with prompt improvement in her hematocrit. We have been unable to elicit any history of prior transfusion or pregnancy in this patient, and her case appears to be one of rapid sensitization due in part to administration of large this
PE in the Management of DHTR
quantities (8 units) of antigen-positive RBCs over a short period of time ( 12 days). The second patient, who had a much more rapid development of DHTR (6 days), is more typical of DHTR patients in that she is both multiparous and multiply-transfused. Her response to plasma exchange was not as dramatic as that of the first patient, probably because of her underlying poor state of health [which included non-A, non-B hepatitis with mild liver dysfunction exacerbated by hypoxia), but the therapy ultimately appears to have reversed the hemolytic episode. Most cases of DHTR are very mild, some consisting only of laboratory evidence of transient hemolysis, as outlined above. On the other hand, some cases are more severe, and several deaths due primarily or partially to DHTR have been reported. 2-5 The life-threatening consequences of DHTR are attributable to excessive hemolysis and include hypotension, renal failure, and disseminated intravascular coagulation (DIC). Current treatment of severe DHTR is similar to that of immediate hemolytic transfusion reaction, and includes administration of mannitol and/or furosemide to aid renal function and heparin to prevent or reverse DIC. To our knowledge, plasma exchange has not been reported previously as a therapeutic modality for severe DHTR, but we believe that our cases demonstrate its efficacy. We believe that plasma removal and replacement is beneficial to these patients because it effects the immediate removal of significant quantities of two harmful substances: the products of hemolysis, notably free hemoglobin, and the circulating anti-RBC antibodies which cause continued hemolysis. Most cases of DHTR will resolve with more conservative management, however, and we recommend that this therapeutic approach be reserved for patients who fail to respond to such management and who remain at risk for significant morbidity or mortality. In our opinion, the identification of such patients is less a matter of specific numerical values than of TS11:1-G
95
clinical evidence that the patient’s ability to tolerate and resolve the DHTR is impaired. We suggest that the following parameters be considered in assessing the need for plasma exchange in a DHTR patient: ill Evidence of overwhelming hemolysis, as discussed above: increase in serum (a) marked indirect bilirubin and LDH; (b) decrease in serum haptoglobin; (c) presence of free hemoglobin in plasma or urine. 12)Severe anemia, e.g. hemoglobin < 7.0 mg/dL or hematocrit < 21%. (3) Evidence of inability to tolerate impairment of oxygen-carrying capacity, such as: (a) decrease in PO,; (b) dyspnea: (c) obtundation or other change in neurologic status: (d) electrocardiographic changes, such as tachycardia or arrhythmia. (4) Evidence of DIC: purpura, mucosal bleeding, increase in fibrin degradation products, decrease in platelet count, etc. (5) Hypotension. In summary, we believe that plasma exchange is helpful in the treatment of severe DHTR because of its ability to effect rapid removal of deleterious products of hemolysis. The decision to employ plasma exchange must be based on an evaluation of the degree to which DHTR is contributing to morbidity in the individual patient involved. REFERENCES 1. Solanki D, McCurdy PR: Delayed hemo-
lytic transfusion reactions: an oftenmissed entity. I Am Med Assoc 1978;
239:729-731. 2. Bove JR: Delayed complications of transfusion. Conn Med 1968; 32~36. 3. Pineda AA, Taswell HF, Brzica SM, Jr: Delayed hemolytic transfusion reaction: an immunologic hazard of blood transfusion. Transfusion 1978; 18:1-7. 4. Hillman NM: Fatal delayed hemolytic transfusion reaction due to antioc + E. Transfusion 1979; 19548551.
96
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