Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Autoimmune hemolytic anemia 2. Drug-induced type Charles A. Horwitz To cite this article: Charles A. Horwitz (1979) Autoimmune hemolytic anemia 2. Drug-induced type, Postgraduate Medicine, 66:3, 199-202, DOI: 10.1080/00325481.1979.11715258 To link to this article: http://dx.doi.org/10.1080/00325481.1979.11715258
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 08 August 2017, At: 17:00
LABORATORY MEDICINE A Series
Autoimmune hernotytic anemia
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
2.
Dn~g-induced
type
The first part of this article, published last month (page 167), discussed the idiopathie warm antibody type of autoimmune hemolytic anemia. This month the author turns his attention to pharmacologie causes, considering the commonly prescribed drugs that may produce this disorder and their mechanisms of action. The fmal part in this series, to be published next month, will focus on the cold antibody type of anemia.
Charles A. Horwitz, MD
Most drugs have low molecular weight and thus elicit antibody responses only when they function as haptens bound to either plasma proteins or membrane proteins on the surface of RBCs. Severa! mechanisms have been implicated in the evolution of drug-induced hemolytic anemia or a positive direct antihuman globulin test (DAT) (figure 1). These mechanisms include drugRBC interaction of the hapten type, immune complex formation, true autoantibody production, and direct alteration of the RBC membrane (table 1). 1-3 Drug-RBC interaction The drug most commonly involved in drug-RBC interactions is penicillin. Penicillin has too low a molecular weight to act alone as an immunogen. However, through its benzylpenicilloyl group 0 (BPO) side chain, it firmly binds to RBC membranes and functions as an immunogenic hapten. In over 90% of patients, this drug-erythrocyte interaction leads to the production of harmless lgM-type antipenicillin antibodies. Occasionally, IgG antibodies against mincir BPO determi-
nants also develop. These lgG antipenicillin molecules are responsible for the occasional case of penicillininduced hemolytic anemia. 1.2 Because they do not activate complement, hemolysis is extravascular and sequestration of lgG-sensitized RBCs occurs in the spleen. With administration of large amounts of penicillin (> 10 million
One of a series of articles on orderlng and lnterpreUng laboratory tests whlch began ln Apr111978
units/day) for at !east seven days, sensitization (ie, a positive DAT) is common (2% to 3% of patients) but clinically significant hemolytic anemia is rare. 4 In vitro confirmation studies with monospecific antihuman globulin reagents reveal that the "coating" substance responsible for the positive DAT is lgG. When the patient's serum or an eluate is incubated with suspensions of normal
RBCs, addition of the antiglobulin reagent results in a negative indirect antiglobulin test (lAT). However, when the same serum is incubated with penicillin-coated or penicillintreated normal RBCs, addition of the antiglobulin reagent results in a positive lAT. Monospecific reagents again reveal the coating substance to be lgG. Carbromal, methadone, chlorpromazine, and possibly sorne of the cephalosporins can also produce a positive DAT by this mechanism. 2 Immune complex formation Drugs that induce immune complex formation (eg, quinine) are rare causes of hemolytic anemia. They are loosely bound to the surface of RBC membranes and act as haptens by combining with plasma proteins, such as albumin. The resultant drug-macromolecule complex acts as an immunogen to elicit the production of lgM antibodies. Free drug can then combine with the lgM antibodies, forming drug-antibody complexes that lodge loosely on the surface of circulating erythrocytes. Complement is attracted to the complex, and the complement cascade is activated. 5 -7 Alternatively, the complex may activate complement directly in plasma, with
continued VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
199
LABORATORY MBDICINE CONTINUED
Atter administration of large amounts of penicillin tor at least sevan days, sensitization of erythrocytes (ie, positive direct antiglobulin test) may occur but clinically signiticant hemolytic anemia is rare.
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Teble1. Mecheni1m1 of drug-induced eutoimmune hemolytic anemie Mecheni1m
Drug••
Direct entiglobulin tnt (DAT)/Coetil'lg IUballnce
Indirect entiglobulin tnt
Clinicel importance
Drug-RBC interaction (firm binding between drug and RBC membrane)
Penlcillin, posslbly carbromal
Positive/lgG
Positive wlth penicillintreated normal RBCs
Occasional cause of hemolytic anemia, with extravascular sequestration of cells
Immune complex formation (loose drug-RBC bindlng)
Quinine, phenacetln, isoniazid
Positive/Complement
Positive with quininetreated normal RBCs
Rare cause of hemolytic anemia, with intravascular hemolysis
Autoantibody production (malnly against Rh antlgen)
Methyldopa, mefenamic acld
Positive/lgG
Positive with normal RBCs (le, true autoantibodies)
Common cause of positive DA T (20% of methyldopa-treated patients); rare cause of hemolytic anemia, probably with extravascular sequestration
Drug alteration of RBC membrane
Cephalosporins
Positive/lgG, posslbly complement
May or may not be positive with cephalosporintreated normal RBCs
Common cause of positive DAT (4% of cephalothin-treated patients); rare cause of hemolytic anemia
•Most common causative agents are listed.
Table 2. Antiglobulin tnt dell in 70-yllll'-old women receiving methyldope THt Direct Polyspeciflc antlserum Monospeclflc lgG Monospeclfic complement (C3) Monospeciflc lgM and lgA Indirect Normal RBCs (not deleted) (ni) Partially deleted RBCs (-d-) Completely deleted RBCs(null) U-negative RBCs
ReeuH Positive Positive Negative Negative
Positive• Negative• Negative• Negative•
•Results with bath serum and eluate.
200
complement then attaching to circulating RBCs (innocent bystanders). Hemolytic anemia has been reported to occur rarely by similar mechanisms in patients taking acetaminophen, aminopyrine, chlorpropamide, dipyrone, hydralazine, insulin, isoniazid, melphalan, paraaminosalicylic acid, phenacetin, quinidine, stibophen, streptomycin, sulfonamides, thiazides, and tolbutamide and in those exposed to various insecticides. Readministration of the drug in very small doses may again trigger a hemolytic process. Confirmatory in vitro studies re-
veal that the positive DAT is due to complement alone on the surface of RBCs. When the patient's serum or an eluate is tested against suspensions of normal RBCs, addition of the antihuman globulin reagent results in a negative lAT. However, when the same serum is tested against quinine-sensitized normal RBCs, addition of the antiglobulin reagent results in a positive lAT. Thus, with bath penicillin- and quinine-induced reactions, normal RBCs must be presensitized with ~he offending drug before addition of the patient's serum and of the antiglobulin reagent reproduces the positive lAT.
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
ln the innocent-bystander type of sensitization, a positive DAT is due to a complement coating alone on the surface of RBCs.
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Autoantibody production The antihypertensive agent methyldopa characteristically induces a positive DAT in 15% to 20% of patients receiving this drug in high dosage for three to six months. Autoimmune hemolytic anemia develops in Jess than 1% of these patients. When methyldopa therapy is discontinued, the hemolytic process subsides in 7 to 14 days; however, the DAT may remain positive for up to severa! years. In patients with a positive DA T without clinically obvious hemolytic anemia, methyldopa can be continued but periodic checks for anemia should be made. Methyldopa-induced autoantibodies characteristically have specificities in the Rh system and may be either simple or complex. Complex autoantibodies are directed against nondeleted (ni), partially deleted (pdl), or deleted (dl) or Rh null cells or against antigens such as Wrb or U. Circulating autoantibodies may be found alone, but are more likely to be found in association with severa! other autoantibodies (eg, anti-e in association with anti-Wrb and anti-pdl) .7.8 Monospecific antiglobulin reagents show that the coating substance on the patient's RBCs is lgG alone, ie, not complement or other immunoglobulins. Levodopa and mefenamic acid
Charles A. Horwitz Dr Horwitz is associate pathologist, Mount Sinai Hospital, and associa te professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis.
Figure 1. Steps in direct antihuman globulin test (Coombs' test) to detect evidence for autoimmunity against RBCs. a. Preparation. b. Centrifugation. c. Addition of antiglobulin reagent. d. End point.
may also cause a positive DA T by a mechanism similar to that of methyldopa. Case history---A 70-year-old woman was admitted for elective arthroplasty of the left hip. Symptoms of severe osteoarthritis had been present for over 15 years, and recently pain had limited her ability to walk without aid. During routine preoperative evaluation, cross-matching was difficult. Investigation revealed a positive DA T. An autocontrol test was also positive. Benign essential hypertension, present for over ten years, was weil controlled with acetazolamide, given twice daily, and methyldopa, 250 mg three or four
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
times daily. Radical mastectomy had been performed at age 52 for mammary carcinoma and partial colectomy at age 65 for carcinoma of the colon. In view of the history of methyldopa therapy, further studies were performed (table 2). These data were consistent with methyldopainduced autoantibody production. Similar antibodies are encountered in the serum of patients with the idiopathie warm antibody type of autoimmune hemolytic anemia (August issue, page 167) and can be demonstrated in an lAT against panels of normal erythrocytes without the in vitro addition of methyldopa. When continued 201
LABORATORY MEDICINE CONTINUED
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Methyldopa causes a positive DAT in up to 20% of patients, while hemolytic anemia occurs in only about 1% of these. The hemolytic process subsides within two weeks atter therapy is discontinued, but the DAT may remain positive for several years.
surgery was rescheduled, the major cross-match procedure again showed ali donor units to react with the patient's serum. However, typespecifie blood was finally released, since no underlying alloantibodies were detected and the reactivity of donor units with the patient's serum was no greater than that of the patient 's own erythrocytes and serum (ie, the autocontrol). Subsequently, a Harris-type prosthesis was placed into the left hip, at which time 3 units of whole blood was administered without complications. At age 71, while still receiving methyldopa (500 mg twice daily), the patient underwent corneal transplantation. Four months later, she was readmitted for treatment of an infection that involved the transplant. At that time, the DAT was still positive (3 + ), hemoglobin was 13.6 gmjdl, and hematocrit was 40.8%. Additional studies on consecutive days showed corrected reticulocyte counts of 2.3%, 3.8%, and 4.6%. Haptoglobin levels varied
from 30 to 50 mg/dl. Her physician judged such data to be consistent with subclinical hemolysis and withheld further methyldopa therapy. Direct alteration of RBC membrane Cephalothin, a semisynthetic cephalosporin, can also induce a positive DA T. The mechanisms are poorly understood. At low dilutions of serum ( 1:4 to 1:8), nonimmunologic binding of lgG, C3, and albumin and other serum proteins with erythrocytes occurs. However, eluate studies suggest that an immune process may also be partly responsible for the sensitization of RBCs. (Eluates from severa! patients reacted with penicillin- or cephalothintreated RBCs but not with noncoated erythrocytes.) Thus, both immune and nonimmune mechanisms may be responsible for the cephalothin-induced positive DA T. In a study in which cephalothin was administered for a mean of 5.5 days, 4% of patients had a positive DA T. 9 Hemolytic anemia is rare.
Summary A "ariety of commonly prescribed drugs can produce a positi"e direct antiglobulin test, but the incidence of actual drug-induced hemolytic anemia is low. Of the four mechanisms which may be responsible, only one involves autoantibody production; the others include drug-RBC interaction of the hapten type, immune complex formation, and direct alteration of the RBC membrane.
Next month: Cold autoimmune hemolytic anemia.
Series coordinator: M. Desmond Burke, MD, associate pathologist, Mount Sinai Hospital, and associate professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis.
Address reprint requests to Charles A. Horwitz, MD, Mount Sinai Hospital, 2215 Park Ave, Minneapolis, MN 55404.
References 1. Croft JD Jr et al: Coombs'-test positivity induced by drugs: Mechanisms of immunologie reactions and red cell destruction. Ann Intern Med 68:176-187, 1968 2. Worlledge SM: Immune drug-induced hemolytic anemias. Sernin Hematol 10:327344, 1973 3. lssitt PD: Auto-immune hemolytic anemia. Am J Med Technol 40:479-495, 1974 4. Nesmith LW, Da~is JW: Hemolytic anemia caused by penicillin: Report of a case in which antipenicillin antibodies cross-reacted with cephalothin sodium. JAMA 203:27-30,
202
1968 S. Shulman NR: A mechanism of cell destruction in individuals sensitized to foreign antigens and its implications in auto-immunity. Combined clinical staff conference at the National Institutes of Health. Ann lntern Med 60:506-521, 1964 6. WorUedge SM: Immune drug-induced haemolytic anemias. Sernin Hematol 6:181200, 1969 7. Swisher SN, Burka ER: Drug reactions involving antibodies reacting with erythrocytes. In Williams W J et al (Editors): Hema-
tology. Ed 2. New York, McGraw-Hill Book Co, 1977, pp 605-610 8. Issitt PD et al: Anti-Wrb and other autoantibodies responsible for positive direct antiglobulin tests in 150 individuals. Br J Haematol 66:5-18, 1976 9. Spath P et al: Studies on the immune response to penicillin and cephalothin in humans. Il. lmmunohematologic reactions to cephalothin administration. J Immunol 107: 860-869, 1971
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Autoimmune hemolytic anemia 2. Drug-induced type Charles A. Horwitz To cite this article: Charles A. Horwitz (1979) Autoimmune hemolytic anemia 2. Drug-induced type, Postgraduate Medicine, 66:3, 199-202, DOI: 10.1080/00325481.1979.11715258 To link to this article: http://dx.doi.org/10.1080/00325481.1979.11715258
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 08 August 2017, At: 17:00
LABORATORY MEDICINE A Series
Autoimmune hernotytic anemia
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
2.
Dn~g-induced
type
The first part of this article, published last month (page 167), discussed the idiopathie warm antibody type of autoimmune hemolytic anemia. This month the author turns his attention to pharmacologie causes, considering the commonly prescribed drugs that may produce this disorder and their mechanisms of action. The fmal part in this series, to be published next month, will focus on the cold antibody type of anemia.
Charles A. Horwitz, MD
Most drugs have low molecular weight and thus elicit antibody responses only when they function as haptens bound to either plasma proteins or membrane proteins on the surface of RBCs. Severa! mechanisms have been implicated in the evolution of drug-induced hemolytic anemia or a positive direct antihuman globulin test (DAT) (figure 1). These mechanisms include drugRBC interaction of the hapten type, immune complex formation, true autoantibody production, and direct alteration of the RBC membrane (table 1). 1-3 Drug-RBC interaction The drug most commonly involved in drug-RBC interactions is penicillin. Penicillin has too low a molecular weight to act alone as an immunogen. However, through its benzylpenicilloyl group 0 (BPO) side chain, it firmly binds to RBC membranes and functions as an immunogenic hapten. In over 90% of patients, this drug-erythrocyte interaction leads to the production of harmless lgM-type antipenicillin antibodies. Occasionally, IgG antibodies against mincir BPO determi-
nants also develop. These lgG antipenicillin molecules are responsible for the occasional case of penicillininduced hemolytic anemia. 1.2 Because they do not activate complement, hemolysis is extravascular and sequestration of lgG-sensitized RBCs occurs in the spleen. With administration of large amounts of penicillin (> 10 million
One of a series of articles on orderlng and lnterpreUng laboratory tests whlch began ln Apr111978
units/day) for at !east seven days, sensitization (ie, a positive DAT) is common (2% to 3% of patients) but clinically significant hemolytic anemia is rare. 4 In vitro confirmation studies with monospecific antihuman globulin reagents reveal that the "coating" substance responsible for the positive DAT is lgG. When the patient's serum or an eluate is incubated with suspensions of normal
RBCs, addition of the antiglobulin reagent results in a negative indirect antiglobulin test (lAT). However, when the same serum is incubated with penicillin-coated or penicillintreated normal RBCs, addition of the antiglobulin reagent results in a positive lAT. Monospecific reagents again reveal the coating substance to be lgG. Carbromal, methadone, chlorpromazine, and possibly sorne of the cephalosporins can also produce a positive DAT by this mechanism. 2 Immune complex formation Drugs that induce immune complex formation (eg, quinine) are rare causes of hemolytic anemia. They are loosely bound to the surface of RBC membranes and act as haptens by combining with plasma proteins, such as albumin. The resultant drug-macromolecule complex acts as an immunogen to elicit the production of lgM antibodies. Free drug can then combine with the lgM antibodies, forming drug-antibody complexes that lodge loosely on the surface of circulating erythrocytes. Complement is attracted to the complex, and the complement cascade is activated. 5 -7 Alternatively, the complex may activate complement directly in plasma, with
continued VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
199
LABORATORY MBDICINE CONTINUED
Atter administration of large amounts of penicillin tor at least sevan days, sensitization of erythrocytes (ie, positive direct antiglobulin test) may occur but clinically signiticant hemolytic anemia is rare.
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Teble1. Mecheni1m1 of drug-induced eutoimmune hemolytic anemie Mecheni1m
Drug••
Direct entiglobulin tnt (DAT)/Coetil'lg IUballnce
Indirect entiglobulin tnt
Clinicel importance
Drug-RBC interaction (firm binding between drug and RBC membrane)
Penlcillin, posslbly carbromal
Positive/lgG
Positive wlth penicillintreated normal RBCs
Occasional cause of hemolytic anemia, with extravascular sequestration of cells
Immune complex formation (loose drug-RBC bindlng)
Quinine, phenacetln, isoniazid
Positive/Complement
Positive with quininetreated normal RBCs
Rare cause of hemolytic anemia, with intravascular hemolysis
Autoantibody production (malnly against Rh antlgen)
Methyldopa, mefenamic acld
Positive/lgG
Positive with normal RBCs (le, true autoantibodies)
Common cause of positive DA T (20% of methyldopa-treated patients); rare cause of hemolytic anemia, probably with extravascular sequestration
Drug alteration of RBC membrane
Cephalosporins
Positive/lgG, posslbly complement
May or may not be positive with cephalosporintreated normal RBCs
Common cause of positive DAT (4% of cephalothin-treated patients); rare cause of hemolytic anemia
•Most common causative agents are listed.
Table 2. Antiglobulin tnt dell in 70-yllll'-old women receiving methyldope THt Direct Polyspeciflc antlserum Monospeclflc lgG Monospeclfic complement (C3) Monospeciflc lgM and lgA Indirect Normal RBCs (not deleted) (ni) Partially deleted RBCs (-d-) Completely deleted RBCs(null) U-negative RBCs
ReeuH Positive Positive Negative Negative
Positive• Negative• Negative• Negative•
•Results with bath serum and eluate.
200
complement then attaching to circulating RBCs (innocent bystanders). Hemolytic anemia has been reported to occur rarely by similar mechanisms in patients taking acetaminophen, aminopyrine, chlorpropamide, dipyrone, hydralazine, insulin, isoniazid, melphalan, paraaminosalicylic acid, phenacetin, quinidine, stibophen, streptomycin, sulfonamides, thiazides, and tolbutamide and in those exposed to various insecticides. Readministration of the drug in very small doses may again trigger a hemolytic process. Confirmatory in vitro studies re-
veal that the positive DAT is due to complement alone on the surface of RBCs. When the patient's serum or an eluate is tested against suspensions of normal RBCs, addition of the antihuman globulin reagent results in a negative lAT. However, when the same serum is tested against quinine-sensitized normal RBCs, addition of the antiglobulin reagent results in a positive lAT. Thus, with bath penicillin- and quinine-induced reactions, normal RBCs must be presensitized with ~he offending drug before addition of the patient's serum and of the antiglobulin reagent reproduces the positive lAT.
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
ln the innocent-bystander type of sensitization, a positive DAT is due to a complement coating alone on the surface of RBCs.
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Autoantibody production The antihypertensive agent methyldopa characteristically induces a positive DAT in 15% to 20% of patients receiving this drug in high dosage for three to six months. Autoimmune hemolytic anemia develops in Jess than 1% of these patients. When methyldopa therapy is discontinued, the hemolytic process subsides in 7 to 14 days; however, the DAT may remain positive for up to severa! years. In patients with a positive DA T without clinically obvious hemolytic anemia, methyldopa can be continued but periodic checks for anemia should be made. Methyldopa-induced autoantibodies characteristically have specificities in the Rh system and may be either simple or complex. Complex autoantibodies are directed against nondeleted (ni), partially deleted (pdl), or deleted (dl) or Rh null cells or against antigens such as Wrb or U. Circulating autoantibodies may be found alone, but are more likely to be found in association with severa! other autoantibodies (eg, anti-e in association with anti-Wrb and anti-pdl) .7.8 Monospecific antiglobulin reagents show that the coating substance on the patient's RBCs is lgG alone, ie, not complement or other immunoglobulins. Levodopa and mefenamic acid
Charles A. Horwitz Dr Horwitz is associate pathologist, Mount Sinai Hospital, and associa te professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis.
Figure 1. Steps in direct antihuman globulin test (Coombs' test) to detect evidence for autoimmunity against RBCs. a. Preparation. b. Centrifugation. c. Addition of antiglobulin reagent. d. End point.
may also cause a positive DA T by a mechanism similar to that of methyldopa. Case history---A 70-year-old woman was admitted for elective arthroplasty of the left hip. Symptoms of severe osteoarthritis had been present for over 15 years, and recently pain had limited her ability to walk without aid. During routine preoperative evaluation, cross-matching was difficult. Investigation revealed a positive DA T. An autocontrol test was also positive. Benign essential hypertension, present for over ten years, was weil controlled with acetazolamide, given twice daily, and methyldopa, 250 mg three or four
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
times daily. Radical mastectomy had been performed at age 52 for mammary carcinoma and partial colectomy at age 65 for carcinoma of the colon. In view of the history of methyldopa therapy, further studies were performed (table 2). These data were consistent with methyldopainduced autoantibody production. Similar antibodies are encountered in the serum of patients with the idiopathie warm antibody type of autoimmune hemolytic anemia (August issue, page 167) and can be demonstrated in an lAT against panels of normal erythrocytes without the in vitro addition of methyldopa. When continued 201
LABORATORY MEDICINE CONTINUED
Downloaded by [Australian Catholic University] at 17:00 08 August 2017
Methyldopa causes a positive DAT in up to 20% of patients, while hemolytic anemia occurs in only about 1% of these. The hemolytic process subsides within two weeks atter therapy is discontinued, but the DAT may remain positive for several years.
surgery was rescheduled, the major cross-match procedure again showed ali donor units to react with the patient's serum. However, typespecifie blood was finally released, since no underlying alloantibodies were detected and the reactivity of donor units with the patient's serum was no greater than that of the patient 's own erythrocytes and serum (ie, the autocontrol). Subsequently, a Harris-type prosthesis was placed into the left hip, at which time 3 units of whole blood was administered without complications. At age 71, while still receiving methyldopa (500 mg twice daily), the patient underwent corneal transplantation. Four months later, she was readmitted for treatment of an infection that involved the transplant. At that time, the DAT was still positive (3 + ), hemoglobin was 13.6 gmjdl, and hematocrit was 40.8%. Additional studies on consecutive days showed corrected reticulocyte counts of 2.3%, 3.8%, and 4.6%. Haptoglobin levels varied
from 30 to 50 mg/dl. Her physician judged such data to be consistent with subclinical hemolysis and withheld further methyldopa therapy. Direct alteration of RBC membrane Cephalothin, a semisynthetic cephalosporin, can also induce a positive DA T. The mechanisms are poorly understood. At low dilutions of serum ( 1:4 to 1:8), nonimmunologic binding of lgG, C3, and albumin and other serum proteins with erythrocytes occurs. However, eluate studies suggest that an immune process may also be partly responsible for the sensitization of RBCs. (Eluates from severa! patients reacted with penicillin- or cephalothintreated RBCs but not with noncoated erythrocytes.) Thus, both immune and nonimmune mechanisms may be responsible for the cephalothin-induced positive DA T. In a study in which cephalothin was administered for a mean of 5.5 days, 4% of patients had a positive DA T. 9 Hemolytic anemia is rare.
Summary A "ariety of commonly prescribed drugs can produce a positi"e direct antiglobulin test, but the incidence of actual drug-induced hemolytic anemia is low. Of the four mechanisms which may be responsible, only one involves autoantibody production; the others include drug-RBC interaction of the hapten type, immune complex formation, and direct alteration of the RBC membrane.
Next month: Cold autoimmune hemolytic anemia.
Series coordinator: M. Desmond Burke, MD, associate pathologist, Mount Sinai Hospital, and associate professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis.
Address reprint requests to Charles A. Horwitz, MD, Mount Sinai Hospital, 2215 Park Ave, Minneapolis, MN 55404.
References 1. Croft JD Jr et al: Coombs'-test positivity induced by drugs: Mechanisms of immunologie reactions and red cell destruction. Ann Intern Med 68:176-187, 1968 2. Worlledge SM: Immune drug-induced hemolytic anemias. Sernin Hematol 10:327344, 1973 3. lssitt PD: Auto-immune hemolytic anemia. Am J Med Technol 40:479-495, 1974 4. Nesmith LW, Da~is JW: Hemolytic anemia caused by penicillin: Report of a case in which antipenicillin antibodies cross-reacted with cephalothin sodium. JAMA 203:27-30,
202
1968 S. Shulman NR: A mechanism of cell destruction in individuals sensitized to foreign antigens and its implications in auto-immunity. Combined clinical staff conference at the National Institutes of Health. Ann lntern Med 60:506-521, 1964 6. WorUedge SM: Immune drug-induced haemolytic anemias. Sernin Hematol 6:181200, 1969 7. Swisher SN, Burka ER: Drug reactions involving antibodies reacting with erythrocytes. In Williams W J et al (Editors): Hema-
tology. Ed 2. New York, McGraw-Hill Book Co, 1977, pp 605-610 8. Issitt PD et al: Anti-Wrb and other autoantibodies responsible for positive direct antiglobulin tests in 150 individuals. Br J Haematol 66:5-18, 1976 9. Spath P et al: Studies on the immune response to penicillin and cephalothin in humans. Il. lmmunohematologic reactions to cephalothin administration. J Immunol 107: 860-869, 1971
VOL 66/NO 3/SEPTEMBER 1979/POSTGRADUATE MEDICINE
