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Hemolytic anemia following intravenous gamma globulin administration
Hemolytiti Anemia following Intravenous Gamma Globulin Administration
ALAN G. BROX, M.D.. DENIS COURNOYER, M.D.. MARION STBRNBACH, M.D. GWENDOLINE SPURLL, M.D. Montreal,
Quebec,
Canada
A young homosexual man with immune thrombocytopenia recently had transient intravascular hemolysis during intravenous gamma globulin treatment. The hemolysis, manifested by a sharp decrease in hemoglobin and by a direct Coombs’ test with a positive result, was mediated by anti-A antibody present in the gamma globulin preparation. In view of the increasing use of intravenous gamma globulin in the treatment of patients with immune cytopenia, this problem may result in crossmatching difficulties and should be recognized as a potential complication of therapy. High-dose intravenous immune globulin is effective in raising the platelet count in patients with immune thrombocytopenia. This treatment is remarkably free of side effects, but compensated hemolysis has been reported [ 11. We report the case of a young homosexual man with immune thrombocytopenia, who, during treatment with high-dose intravenous immune globulin, demonstrated transient intravascular hemolysis, which appeared to be mediated by anti-A antibody present in the commercial gamma globulin preparation.
CASE REPORT
From the Division of Hematoloav. Roval Victoria Hospital, McGill University, and the Canadian Red Cross, Rlood Transfusion Service, Montreal, Quebec, Canada. Requests for reprints should be addressed to ,Dr. Alan G. Brox, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A lA1, Canada. Manuscript submitted November 4, 1985, and accepted December 10, 1985.
A 30-year-old homosexual man presented with epistaxis, gum bleeding, and purpura. History and physical examination were unremarkable, apart from purpura. Laboratory investigation showed a normal hemoglobin level and white blood cell count and a platelet count of 2,000/1*1. Bone marrow aspiration showed increased megakaryocytes. The lymphocyte T4IT8 ratio was 0.4 (normal 1.5 to 2) and total TCpositive cells were 320. Tests for hepatitis B surface antigen, syphilis, antinuclear antibody, rheumatoid factor, C3, C4, and serum immune globulins and serum protein electrophores/s, gave negative results. Antiplatelet antibody was not detected. Treatment was instituted with prednisone, 100 mg per day. Because there was no response, prednisone was discontinued and the decision was made to procede with splenectomy. Intravenous immune, globulin, 400 mg/kg per day for seven days (Immuno endoglobulin in Europe), was given in an attempt to increase his platelet count prior to splenectomy. No other blood products were given. Over the period of intravenous immune globulin administration, the hemoglobin level fell from 14.5 to 10.0 g/dl (Figure 1). Direct and indirect Coombs’ tests had positive results. Spherocytes and polydhromasia appeared in the peripheral smear, and the serum haptoglobin level fell to 30 mg/dl. Serum showed anti-blood group A activity and no reactivity with group 0 antibody screening cells. Antibody eluted from the patient’s red blood cells by Rubin elution showed Al specificity. One of the two lots of intravenous immune globulin administered to the patient had an anti-A titer of 16, and the antibody activity was neutralized by A substance.
March
1987
The American
Journal
of Medicine
Volume
82
633
HEMOLYTIC
ANEMIA
AFTER
INTRAVENOUS
GAMMA
iv IgG 400mg/Kg I-
15.0-r
GLOBULIN-BROX
ET AL
Splenectomy
00 -l
-5OOK o..........o Hb
I 14.0--
i’****Q t,+ 3. 5
13.0--
d
l
‘5, 5 .P%% 5,” %$ ‘0...0
12.0 --
-•
PLAT
--400K
.J\ 5. \
ll.O--
_- 300K \
P” %, p *a,& -j ;-
\ Q-.. ,Go “‘....a #1,,,,,.,o
10.0 --
; $ \ : %%,;B I. -6
9.0--
\
.o a ,.. 5..,*,&* .
--ZOOK
--lOOK
/ *.-./* .-.-.-.-./-+ I I I 1 2 3
I 4
I 5
I 6
I 7
I 8
I I I I I I I I I I I I I I I III III 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
A
++
Al
+++
A2
++-
Screen Cells
-
Direct Coomb’s
-
Figure 1. Patient’s bin; PLAT = platelet
course and evaluation count.
followins
administration
The other lot was not available for testing. Splenectomy was performed. Following discontinuation of the intravenous immune globulin, the hemoglobin level returned to normal and the Coombs’ result became negative.
Intravenous immune globulin is increasingly used in the treatment of patients with immune thrombocytopenia [2]. Possible mechanisms of action of intravenous immune globulin in this setting include reticuloendothelial blockade by freed IgG, or by IgG bound to red blood cells [3]. Intravenous preparations of IgG are Cohn fraction II fractions prepared from large pools of plasma. The preparations consist mainly of IgG but may contain small amounts of IgA and IgM. Lots are screened for isoagglutinin activity, and the titer must be 16 or less. The batch of intravenous immune globulin that our patient received had an anti-A titer of 16. The patient received 2.8 g/kg of IgG, which would, if distributed in total extracellular water, give enough anti-A to explain the positive Coombs’ result. The observed decrease in hemoglobin and haptoglobin levels and the changes in the peripheral smear are most consistent with hemolysis due to anti-A activity in the transfused IgG. No other blood products were given during the period when the hemolysis appeared. The Coombs’ test result reverted to negative in a time frame consistent with passively acquired antibody. Salama et al [I] have reported decreased haptoglobin
March
1987
The American
Journal
of Medicine
Volume
-
+
+
of intravenous
weak
immune globulin
(iv IgGj. Hb = hemogle
I
levels and mild reticulocytosis without a decrease in hemoglobin levels in normal volunteers receiving intravenous immune globulin. They concluded that clinically insignificant hemolysis may occur after intravenous immune globulin administration, but that it is well compensated. Other reports of the use of intravenous immune globulin have not discussed hemolysis; however, in general, Coombs’ results and haptoglobin levels have not been determined [4,5]. Our patient, a homosexual man, had an abnormal T4/T8 ratio. Morris et al [6] have shown that homosexuals with immune thrombocytopenia differ from other patients with immune thrombocytopenia, in that homosexual patients have higher platelet-associated IgG and complement levels, but no serum antiplatelet antibodies. Morris et al have suggested that the immune platelet clearance may be due to Fc receptor-bound immune complexes. It is possible that the immunologic abnormalities in these patients also make the development of hemolysis more likely, The unexpected positive result in the indirect Coombs’ test in this patient created considerable difficulty in crossmatching prior to surgery, and resulted in delay of surgery. We suggest that Coombs’ results and haptoglobin levels be followed in patients treated with intravenous immune globulin, and that serum samples be saved from all patients who receive intravenous immune globulin to simplify future crossmatches.
COMMENTS
634
-
TIME(days)
82
HEMOLYTIC
ANEMIA
AFTER
INTRAVENOUS
GAMMA
GLOBULIN-BROX
ET AL
REFERENCES 1.
2.
3.
4.
Salama A, Mueller-Eckhardt G, Kiefel V: Effect of intravenous immunoglobulins in immune thrombocytopenia. Lancet 1983; II: 193-195. Oral A, Nusbacher J, Hill JB, Lewis JH: Intravenous gamma globulin in the treatment of chronic idiopathic thrombocytopenic purpura in adults. Am J Med 1984; 76(suppl 3A): 187-192. Bussel JB, Hilgartner MW: The use and mechanism of action of intravenous immunoglobulin in the treatment of immune hematologic disease. Br J Haematol 1984; 56: 1-7. Winiarski J, Kreuger A, Ejderhamn J, Holm G: High dose
5.
6.
March
1987
intravenous immunoglobulin reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura. Stand J Haematol 1983; 31: 342-343. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 1982; 306: 1254-1258. Morris L, Distenfeld A, Amorosi E, Karpatkin S: Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med 1982; 96: 714-717.
The American
Journal
of Medicine
Volume
82
835
ALAN G. BROX, M.D.. DENIS COURNOYER, M.D.. MARION STBRNBACH, M.D. GWENDOLINE SPURLL, M.D. Montreal,
Quebec,
Canada
A young homosexual man with immune thrombocytopenia recently had transient intravascular hemolysis during intravenous gamma globulin treatment. The hemolysis, manifested by a sharp decrease in hemoglobin and by a direct Coombs’ test with a positive result, was mediated by anti-A antibody present in the gamma globulin preparation. In view of the increasing use of intravenous gamma globulin in the treatment of patients with immune cytopenia, this problem may result in crossmatching difficulties and should be recognized as a potential complication of therapy. High-dose intravenous immune globulin is effective in raising the platelet count in patients with immune thrombocytopenia. This treatment is remarkably free of side effects, but compensated hemolysis has been reported [ 11. We report the case of a young homosexual man with immune thrombocytopenia, who, during treatment with high-dose intravenous immune globulin, demonstrated transient intravascular hemolysis, which appeared to be mediated by anti-A antibody present in the commercial gamma globulin preparation.
CASE REPORT
From the Division of Hematoloav. Roval Victoria Hospital, McGill University, and the Canadian Red Cross, Rlood Transfusion Service, Montreal, Quebec, Canada. Requests for reprints should be addressed to ,Dr. Alan G. Brox, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A lA1, Canada. Manuscript submitted November 4, 1985, and accepted December 10, 1985.
A 30-year-old homosexual man presented with epistaxis, gum bleeding, and purpura. History and physical examination were unremarkable, apart from purpura. Laboratory investigation showed a normal hemoglobin level and white blood cell count and a platelet count of 2,000/1*1. Bone marrow aspiration showed increased megakaryocytes. The lymphocyte T4IT8 ratio was 0.4 (normal 1.5 to 2) and total TCpositive cells were 320. Tests for hepatitis B surface antigen, syphilis, antinuclear antibody, rheumatoid factor, C3, C4, and serum immune globulins and serum protein electrophores/s, gave negative results. Antiplatelet antibody was not detected. Treatment was instituted with prednisone, 100 mg per day. Because there was no response, prednisone was discontinued and the decision was made to procede with splenectomy. Intravenous immune, globulin, 400 mg/kg per day for seven days (Immuno endoglobulin in Europe), was given in an attempt to increase his platelet count prior to splenectomy. No other blood products were given. Over the period of intravenous immune globulin administration, the hemoglobin level fell from 14.5 to 10.0 g/dl (Figure 1). Direct and indirect Coombs’ tests had positive results. Spherocytes and polydhromasia appeared in the peripheral smear, and the serum haptoglobin level fell to 30 mg/dl. Serum showed anti-blood group A activity and no reactivity with group 0 antibody screening cells. Antibody eluted from the patient’s red blood cells by Rubin elution showed Al specificity. One of the two lots of intravenous immune globulin administered to the patient had an anti-A titer of 16, and the antibody activity was neutralized by A substance.
March
1987
The American
Journal
of Medicine
Volume
82
633
HEMOLYTIC
ANEMIA
AFTER
INTRAVENOUS
GAMMA
iv IgG 400mg/Kg I-
15.0-r
GLOBULIN-BROX
ET AL
Splenectomy
00 -l
-5OOK o..........o Hb
I 14.0--
i’****Q t,+ 3. 5
13.0--
d
l
‘5, 5 .P%% 5,” %$ ‘0...0
12.0 --
-•
PLAT
--400K
.J\ 5. \
ll.O--
_- 300K \
P” %, p *a,& -j ;-
\ Q-.. ,Go “‘....a #1,,,,,.,o
10.0 --
; $ \ : %%,;B I. -6
9.0--
\
.o a ,.. 5..,*,&* .
--ZOOK
--lOOK
/ *.-./* .-.-.-.-./-+ I I I 1 2 3
I 4
I 5
I 6
I 7
I 8
I I I I I I I I I I I I I I I III III 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
A
++
Al
+++
A2
++-
Screen Cells
-
Direct Coomb’s
-
Figure 1. Patient’s bin; PLAT = platelet
course and evaluation count.
followins
administration
The other lot was not available for testing. Splenectomy was performed. Following discontinuation of the intravenous immune globulin, the hemoglobin level returned to normal and the Coombs’ result became negative.
Intravenous immune globulin is increasingly used in the treatment of patients with immune thrombocytopenia [2]. Possible mechanisms of action of intravenous immune globulin in this setting include reticuloendothelial blockade by freed IgG, or by IgG bound to red blood cells [3]. Intravenous preparations of IgG are Cohn fraction II fractions prepared from large pools of plasma. The preparations consist mainly of IgG but may contain small amounts of IgA and IgM. Lots are screened for isoagglutinin activity, and the titer must be 16 or less. The batch of intravenous immune globulin that our patient received had an anti-A titer of 16. The patient received 2.8 g/kg of IgG, which would, if distributed in total extracellular water, give enough anti-A to explain the positive Coombs’ result. The observed decrease in hemoglobin and haptoglobin levels and the changes in the peripheral smear are most consistent with hemolysis due to anti-A activity in the transfused IgG. No other blood products were given during the period when the hemolysis appeared. The Coombs’ test result reverted to negative in a time frame consistent with passively acquired antibody. Salama et al [I] have reported decreased haptoglobin
March
1987
The American
Journal
of Medicine
Volume
-
+
+
of intravenous
weak
immune globulin
(iv IgGj. Hb = hemogle
I
levels and mild reticulocytosis without a decrease in hemoglobin levels in normal volunteers receiving intravenous immune globulin. They concluded that clinically insignificant hemolysis may occur after intravenous immune globulin administration, but that it is well compensated. Other reports of the use of intravenous immune globulin have not discussed hemolysis; however, in general, Coombs’ results and haptoglobin levels have not been determined [4,5]. Our patient, a homosexual man, had an abnormal T4/T8 ratio. Morris et al [6] have shown that homosexuals with immune thrombocytopenia differ from other patients with immune thrombocytopenia, in that homosexual patients have higher platelet-associated IgG and complement levels, but no serum antiplatelet antibodies. Morris et al have suggested that the immune platelet clearance may be due to Fc receptor-bound immune complexes. It is possible that the immunologic abnormalities in these patients also make the development of hemolysis more likely, The unexpected positive result in the indirect Coombs’ test in this patient created considerable difficulty in crossmatching prior to surgery, and resulted in delay of surgery. We suggest that Coombs’ results and haptoglobin levels be followed in patients treated with intravenous immune globulin, and that serum samples be saved from all patients who receive intravenous immune globulin to simplify future crossmatches.
COMMENTS
634
-
TIME(days)
82
HEMOLYTIC
ANEMIA
AFTER
INTRAVENOUS
GAMMA
GLOBULIN-BROX
ET AL
REFERENCES 1.
2.
3.
4.
Salama A, Mueller-Eckhardt G, Kiefel V: Effect of intravenous immunoglobulins in immune thrombocytopenia. Lancet 1983; II: 193-195. Oral A, Nusbacher J, Hill JB, Lewis JH: Intravenous gamma globulin in the treatment of chronic idiopathic thrombocytopenic purpura in adults. Am J Med 1984; 76(suppl 3A): 187-192. Bussel JB, Hilgartner MW: The use and mechanism of action of intravenous immunoglobulin in the treatment of immune hematologic disease. Br J Haematol 1984; 56: 1-7. Winiarski J, Kreuger A, Ejderhamn J, Holm G: High dose
5.
6.
March
1987
intravenous immunoglobulin reduces platelet associated immunoglobulins and complement in idiopathic thrombocytopenic purpura. Stand J Haematol 1983; 31: 342-343. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 1982; 306: 1254-1258. Morris L, Distenfeld A, Amorosi E, Karpatkin S: Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med 1982; 96: 714-717.
The American
Journal
of Medicine
Volume
82
835