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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2523-2529
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Acute onset hemoglobinemia and/or hemoglobinuria and sequelae
following Rho(D) immune globulin intravenous administration
in immune thrombocytopenic purpura patients
Ann Reed Gaines
From the Office of Biostatistics and Epidemiology, Center for
Biologics Evaluation and Research, Food and Drug Administration,
Rockville Pike, Rockville, MD.
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Abstract |
Rho(D) immune globulin intravenous (anti-D IGIV) was
licensed by the United States Food and Drug Administration (FDA) in
March 1995 to treat patients with immune thrombocytopenic purpura
(ITP). Anti-D IGIV induces extravascular hemolysis, an expected adverse reaction that is consistent with the presumed mechanism of action. Between licensure and April 1999, the FDA received 15 reports of
hemoglobinemia and/or hemoglobinuria following anti-D IGIV administration that met the case definition for this review. The mechanism responsible for hemoglobinemia and/or hemoglobinuria is
unexplained. Review of these reports was prompted by the seriousness and the unexpectedness of treatment-associated sequelae experienced by
11 patients. Of these patients, 7 developed sufficient onset or
exacerbation of anemia that orders were written for packed red blood
cell transfusions, although only 6 patients were transfused. Eight
patients experienced the onset or exacerbation of renal insufficiency,
and 2 patients underwent dialysis. One patient died due to
complications of exacerbated anemia. Six patients experienced 2 to 3 sequelae. Absent validated incidence data, a 1.5% estimated incidence
rate from published clinical trial data and a 0.1% estimated reporting
rate from FDA and drug utilization data were calculated for reported
cases of hemoglobinemia and/or hemoglobinuria. This review presents the
first case series of anti-D-IGIV-associated hemoglobinemia and/or
hemoglobinuria and provides pretreatment and posttreatment clinical and
laboratory findings of the case series patients. The primary purpose of
this review is to increase awareness of this potentially serious
occurrence among physicians and health care professionals who manage
ITP patients treated with anti-D IGIV, thereby enabling prompt
recognition and treatment of sequelae.
(Blood. 2000;95:2523-2529)
© 2000 by The American Society of Hematology.
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Introduction |
Rho(D) immune globulin intravenous (anti-D
IGIV) was licensed by the United States Food and Drug Administration
(FDA) in March 1995 for the treatment of immune thrombocytopenic
purpura (ITP) in D-positive, nonsplenectomized children with acute ITP,
children and adults with chronic ITP, and children and adults with ITP secondary to human immunodeficiency virus (HIV) infection.1 The primary mechanism of action of anti-D IGIV in ITP patients is
presumed to involve the Fc blockade. This mechanism involves competitive binding of anti-D-sensitized red blood cells (RBCs) to
macrophage Fc receptors within the spleen, thereby reducing the extent
of sequestration and destruction of the patient's antibody-sensitized platelets.1-7
For the management of ITP, the recommended initial dose of anti-D IGIV
is 50 µg/kg via intravenous administration over 3 to 5 minutes for
patients with a hemoglobin level of at least 100 g/L.1 For
patients with a hemoglobin level of less than 100 g/L, the recommended
initial dose is reduced to 25 to 40 µg/kg to lessen the likelihood of
significantly exacerbating preexisting anemia, particularly in patients
with a hemoglobin level of less than 80 g/L.1 In patients
who respond therapeutically to anti-D IGIV, an increased platelet count
is observed, generally beginning within 1 to 3 days, peaking within 7 to 14 days, and persisting for approximately 30 days.1,2,4,8-11 The dose and frequency of any subsequent
treatment is dependent upon the patient's clinical response to the
initial dose, in conjunction with other
considerations.1,2,4,7
The anti-D contained in a 300-µg vial of anti-D IGIV effects the
sensitization and sequestration of approximately 17 mL of D-positive
RBCs,1 which are presumed to be destroyed primarily via
extravascular hemolysis.1-7 Thus, a decrease in hemoglobin is a known therapeutic consequence1,2,4-8,10-14 and is
listed in the package insert as an expected adverse event.1
A decrease in hemoglobin may be initially noted within hours of anti-D
IGIV administration,2,7 with a maximum decrease generally
observed within 1-2 weeks.1,2,4,6,8,11-13 Among 137 ITP
patients treated with anti-D IGIV in the clinical trial, the mean
hemoglobin decrease was 17 g/L (range: 4 to 61 g/L), with decreases of
more than 40 g/L (range: 42 to 61 g/L) observed in only 3.7% of those patients.1,6
Anti-D IGIV is produced by stimulating human plasma donors with
D-positive RBCs15,16 and is manufactured from pools of donor plasma to contain more than 90% polyclonal immunoglobulin G
(IgG) anti-D.1,6,15,17,18 Concentrations of
IgG1, IgG2, and IgG3 are comparable
to those of normal serum, and concentrations of IgG4 are
negligible.17 Anti-D IGIV contains low-titered anti-A, anti-B, anti-C, and anti-E blood group antibodies1,17,18 that may be passively acquired and may be detectable in posttreatment direct antiglobulin tests (DAT) and indirect antiglobulin tests (IAT).1 Pharmacokinetic studies indicate that peak levels
of anti-D are achieved within 2 hours of administration of anti-D IGIV
and that the in vivo half-life of anti-D is approximately 24 days.1 Lyophilized anti-D IGIV is stable when stored at 2 to 8°C, and reconstituted anti-D IGIV is stable when stored at room
temperature for 12 hours.1,17
In April 1998 the manufacturer of anti-D IGIV revised the package
insert to note "rare reports of acute onset
hemoglobinuria consistent with intravascular hemolysis," following 5 postmarketing surveillance reports of hemoglobinuria in association
with anti-D IGIV treatment of ITP patients.1 There were 2 other revisions at that time stating that hemoglobinuria was
"possibly accompanied by reversible acute renal impairment" and
that "[s]ome cases [of hemoglobinuria] occurred in patients
receiving red blood cell transfusion concurrently with [anti-D
IGIV]."1
This case series evolved from FDA postmarketing surveillance of adverse
event reports involving possible hemoglobinemia and/or hemoglobinuria
following administration of anti-D IGIV for the ITP indication.
Evaluation of these reports and the subsequent case series development
were prompted primarily by the seriousness and unexpectedness of the
sequelae reported. As defined by the FDA, "serious" includes
medical intervention and initial or prolonged hospitalization, among
other criteria, and "unexpected" refers to adverse events not
listed in the package insert. Furthermore, the hemoglobinemia and/or
hemoglobinuria was unexpected, on the basis of the then-current package
insert, and unexplained by the case series data. The
impetus for this case series review was the FDA's follow-up
investigation of these reports and a review of the literature. Both the
follow-up and the literature suggested that physicians and health care
professionals who manage ITP patients treated with anti-D IGIV might be
relatively unaware of what appears to be an uncommon but a potentially
serious complication.
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Patients and methods |
Case series definition
A case was considered evaluable and was included in the case series
if it involved the acute onset of hemoglobinemia and/or hemoglobinuria
following anti-D IGIV administration for the ITP indication. Acute
onset corresponded to less than or equal to 4 hours following anti-D
IGIV administration. Hemoglobinemia was defined as either an increased
plasma hemoglobin or an anecdotal report of "visibly red serum."
Hemoglobinuria was defined as routine urinalysis results of a positive
reagent strip test for blood and a urinary sediment examination
revealing fewer RBCs than would be expected on the basis of the
positive reagent strip test.19 Positive reagent strip
results were presumed to represent hemoglobinuria, given the context of
hemolysis of anti-D-sensitized RBCs, although myoglobinuria was not
ruled out in all patients.
Sequelae were serious, unexpected adverse events, as defined by the FDA
and based on the March 1995 and April 19981 package
inserts, that occurred in association with hemoglobinemia and/or
hemoglobinuria. Based on those criteria, sequelae included orders
written for transfusion with packed RBCs (PRBCs), onset or exacerbation
of renal insufficiency, renal dialysis, and death.
Frequency estimates of hemoglobinemia and/or hemoglobinuria
associated with anti-D IGIV administration for the ITP indication
The actual incidence of hemoglobinemia and/or hemoglobinuria
associated with anti-D IGIV administered for the ITP indication is
unknown. In the absence of validated incidence data, frequency estimates for incidence rate and incidence were calculated. The incidence rate was defined as the percentage of the US population of
ITP patients treated with anti-D IGIV who experienced hemoglobinemia and/or hemoglobinuria.20 Estimated frequency rates were
termed either estimated incidence rates or estimated reporting rates, depending on the specific limitations of each data source
used.20 Although the incidence of an adverse event is
generally defined as its occurrence per 100 000
patients,20 given the relatively small numbers of patients
from each data source used, estimated incidence was calculated as the
ratio of the estimated frequency rate numerator and denominator.
Two sources of data were a literature report that summarized the
results of ITP patients treated with anti-D IGIV in the clinical trial6 and a composite of clinical studies reported for ITP patients treated with anti-D IGIV.2,4,7,8,10,11,23 The raw
data from each of these data sources were used as the respective
numerators and denominators. FDA data were used as the numerator for
the other frequency estimates, and drug utilization data obtained by
the FDA21,22 were used for the denominator. Drug
utilization data were from 2 IMS Health Incorporated
databases: (1) Provider Perspective,21
1995-1998, which provided prescription purchases by various US
hospitals, health maintenance organizations, and other health care
facilities20 and (2) National Disease and Therapeutic
Index,22 1995-1998, which provided prescription audits from
US physician office-based practices.20 Conversion of the
IMS data to the number of ITP patients treated with anti-D IGIV
required certain broad assumptions that were referenced to anti-D IGIV
literature to the extent possible.
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Results |
Pretreatment profile of patients reported to the FDA
The 15 cases of hemoglobinemia and/or hemoglobinuria that occurred
following anti-D IGIV treatment were distributed across 13 states. None
of the cases had attending physicians and health care facilities in
common. The adverse events for these patients occurred between
September 1995 and March 1999 and were reported to the FDA between May
1996 and April 1999.
The indication for treatment with anti-D IGIV was provided for all 15 patients. For 5 of the 7 pediatric patients, the indication was acute
ITP following viral infection; for 1, the indication was not otherwise
specified ITP; and for the other, the indication was not otherwise
specified thrombocytopenia. For 4 of the 8 adult patients, the
indication was chronic ITP; for 1, the indication was not otherwise
specified ITP; for 2, the indication was not otherwise specified
thrombocytopenia; and for the other, the indication was autoimmune
hemolytic anemia.
One patient was diagnosed with autoimmune hemolytic anemia, and another
patient had suspected autoimmune hemolytic anemia. Evan's syndrome and
autoimmune hemolytic anemia had been ruled out in 2 patients following
a hematologic evaluation that was completed immediately prior to
administration of anti-D IGIV. Two patients had preexisting renal
insufficiency, and 1 patient had previously undergone a splenectomy.
The patients in the case study ranged in age from 3 to 86 years (Table
1). For pediatric patients, the mean age
was 11 years (range: 3 to 17 years). The mean age of adult patients was
59 years (range: 32 to 86 years). Of the 7 pediatric patients, 4 were
female. Of the 8 adult patients, 5 were female. Hemoglobins were
available for all 15 patients, with a mean of 117 g/L and a median of
119 g/L (range: 91 to 149 g/L) (Table 1).
The dose of anti-D IGIV administered was available for all 15 patients
(Table 1). For the 12 patients whose hemoglobin level was greater than
or equal to 100 g/L, the mean dose was 50 µg/kg, with a median dose
of 50 µg/kg (range: 24 to 100 µg/kg). The 3 patients who had a
hemoglobin of less than 100 g/L received a mean dose of 58 µg/kg,
with a median dose of 52 µg/kg (range: 46 to 75 µg/kg). The anti-D
IGIV infusion time was available for 5 patients; the mean infusion time
was 15 minutes, with a median infusion time of 24 minutes (range: 5 to
60 minutes).
ABO and D blood groups were available for 9 patients: 6 were group O, 3 were group A, and all were D-positive. Rh phenotyping was available for
only 1 group O patient, who was cDEe. DATs were available
for 7 patients, and 6 patients tested negative. The DAT of the patient
with diagnosed autoimmune hemolytic anemia was positive for a
cold-reacting antibody and complement. The DAT of the patient with
suspected autoimmune hemolytic anemia was negative. No IATs were available.
Two patients had previously received anti-D IGIV. One patient was
treated approximately 6 months earlier without resulting hemoglobinemia
and/or hemoglobinuria and with a platelet response; the other patient
was treated 1 week earlier, without resulting hemoglobinemia and/or
hemoglobinuria but without a platelet response. Of 12 patients for whom
data were available, 4 had been previously treated with other blood
products, which included PRBCs, platelets, and/or polyspecific IGIV,
and none had experienced hemoglobinemia and/or hemoglobinuria following
administration of those products. None of the patients received anti-D
IGIV concomitantly with any blood products, and none of the 15 patients
were subsequently rechallenged with anti-D IGIV.
Lot numbers were available for the anti-D IGIV administered to 9 patients. There were 10 different lots specified, and only 2 patients received anti-D IGIV from the same lot. For 4 lots reported, the FDA's database included 1 to 2 other adverse
event reports that were unrelated to hemoglobinemia and/or hemoglobinuria.
Posttreatment profile of patients reported to the FDA
The time of onset of signs and/or symptoms was available for 12 patients (range: 35 minutes to 4 hours). The most consistent sign
available across all cases was hemoglobinuria, which was observed in 14 patients. When provided, the urine color ranged from pink to red to
brown to black. The 1 patient who did not experience hemoglobinuria had
an increased serum hemoglobin level and a serum haptoglobin at the
lower limit of the normal range, although pretreatment results were not
available for comparison. Seemingly, in this patient, whose hemoglobin
level decreased 14 g/L, the degree of hemoglobinemia was not sufficient
to deplete his serum haptoglobin and result in hemoglobinuria.
A continuum of symptoms was reported. Of the 12 patients for whom data
were available, 2 patients did not experience any symptoms, while 10 patients exhibited classic symptoms associated with acute hemolytic
transfusion reactions. At one end of the continuum, 1 patient
experienced shaking chills and low back pain but no sequelae. In
contrast, another patient presented with no complaints other than
"bloody urine," which was later determined to be hemoglobinuria, but he experienced sequelae that included transfusion with PRBCs and
the onset of renal insufficiency.
The mean decrease in hemoglobin was available for 14 patients (Table
1). The decrease in hemoglobin was not confounded by PRBC transfusion
in only 8 of these patients; the maximum decrease in hemoglobin
occurred in, at most, 1 week, with a mean decrease of 37 g/L
and a median decrease of 34 g/L (range: 0 to 76 g/L).
Of note are the 2 patients who experienced the extremes of hemoglobin
decreases. One patient developed black urine with 3+ blood and 0 RBCs/hpf within 3 hours following anti-D IGIV administration. Neither
the degree nor the duration of hemoglobinuria was apparently sufficient
to result in a hemoglobin decrease. In another patient, the maximum
hemoglobin decrease occurred 8 days after treatment, but she
experienced ongoing hemolysis for at least 20 days, as evidenced by
persistent hemoglobinuria. Her hemoglobin decrease of 76 g/L may have
been an underestimate of the degree of hemolysis. Hemolysis may have
been moderated by an erythrokinetic response to anemia, which is
suggested by a reticulocyte count of 21.4% 8 days after treatment.
The duration of hemoglobinuria or an approximation thereof was
available for 8 patients (Table 1). Hemoglobinuria persisted 1 day or
less in 2 patients, 2 days or more in 2 patients, 3 days or more in 1 patient, 7 days or more in 2 patients, and 20 days or more in 1 patient. Sequelae were not experienced in 3 of these patients, while
each of the other 5 patients experienced 1 to 2 sequelae. The patient
whose hemoglobinuria persisted 20 days or more experienced no sequelae.
Of the 8 patients whose decrease in hemoglobin was not confounded by
PRBC transfusion, 2 patients experienced an estimated RBC loss less
than or equal to that predicted by the dose of anti-D IGIV
administered. The other 6 patients experienced a mean estimated RBC
loss of 5.8 times that predicted by the dose of anti-D IGIV administered, with a median loss of 5.7 times that predicted (range: 3.0 to 8.5 times that predicted). At one extreme, the patient whose
hemoglobin decreased 76 g/L and whose hemoglobinuria persisted 20 days
or more experienced an estimated RBC loss 3.0 times that predicted by
the 100 µg/kg dose of anti-D IGIV she was given. At the other
extreme, another patient experienced a 27-g/L hemoglobin decrease and
hemoglobinuria that cleared within 7 hours, but his estimated blood
loss was 8.5 times in excess of that predicted by the 53 µg/kg dose
of anti-D IGIV he received.
Of the 15 total patients, 4 experienced no sequelae. The remaining 11 patients experienced at least 1 sequelae that was attributed to anti-D
IGIV administration, and 6 patients experienced various combinations of
2 to 3 concurrent sequelae.
PRBCs were ordered for 7 patients; 1 patient refused transfusion, and
thus only 6 patients were transfused (Table 1). The mean number of
units of PRBCs transfused within hours to days of anti-D IGIV
administration was 3 (range: 1 to 6 units). When specified, patients
were transfused with D-negative PRBCs.
Onset or exacerbation of renal insufficiency was noted in 8 patients: 6 patients had pretreatment renal function within normal limits, and 2 patients had preexisting renal insufficiency. Paired pretreatment and
posttreatment serum creatinine levels were available for 7 of these
patients. The mean increase in the serum creatinine level was 35 mg/L,
with a median increase of 25 mg/L (range: 8.0 to 103 mg/L) (Table 1).
The mean time of onset of the renal insufficiency was approximately 22 hours (range: approximately 2 to 48 hours) following anti-D IGIV
administration. In surviving patients who did not undergo dialysis, the
serum creatinine level peaked within a mean of 5 days (range: 2 to 9 days) and resolved, as evidenced by the return of the serum creatinine
level to baseline, within a mean of 12 days (range: 4 to 23 days). Two
patients died with unresolved renal insufficiency. No renal histology
was available since neither renal biopsies nor autopsies were performed
on any of these patients.
The 17 mg/L peak serum creatinine level for 1 patient belied the fact
that he presented with oliguria; this suggests that he responded to
promptly administered medical intervention. The patient whose peak
serum creatinine level was 110 mg/L and who underwent dialysis 3 times
had pretreatment renal function that was within normal limits.
DATs were available for 7 patients and were obtained 24 to 72 hours
after treatment. Results of 3 DATs were reported only as positive, and
4 were reported as positive for IgG and negative for complement.
Elutions, available for 3 of the latter 4 DATs, revealed only anti-D.
Of possible note is that hemoglobinuria was ongoing for these 3 patients at the time the DATs were obtained. IATs, available for 3 patients, were negative for 2 patients and positive for anti-C in the
known C-negative patient. The results of the latter 3 DATs and the 1 IAT appear to reflect passively acquired anti-D and anti-C,
respectively. But these results do not exclude the possibility that
other IgM-, IgG-, and/or complement-sensitized RBCs may have been
present at the onset of hemoglobinemia and/or hemoglobinuria but were
not detectable 24 to 72 hours posttreatment.
Platelet response following anti-D IGIV treatment was available for 9 patients; 5 patients exhibited an increase in platelet count that
ranged from 75 000-341 000 × 109/L, which was
observed 3 to 7 days after treatment. Of the 4 patients who did not
exhibit a platelet response, 2 had not experienced an increase in
platelet count by 1 week posttreatment, after which no further platelet
counts were available, and 2 had not experienced an increase in
platelet count at 6 weeks posttreatment. However, the hemoglobinemia
and/or hemoglobinuria did not preclude a platelet response in the 5 patients.
Four patients died following anti-D IGIV administration (Table 1). One
patient died 3 days following treatment with anti-D IGIV due to
pulmonary edema and respiratory distress that resulted from exacerbation of anemia; her physician believed that she
would probably have survived had she not refused transfusion. Three patients died from other primary causes 2 to 22 days posttreatment. Although not directly related to the primary cause of death in these 3 patients, the extent to which the 1 to 2 sequelae experienced by each
may have exacerbated their conditions and contributed to their deaths
is unknown.
Frequency estimates of hemoglobinemia and/or hemoglobinuria
following anti-D IGIV administration for the ITP indication
Three sets of frequency estimates (Table
2) were calculated. In the literature
report based on the clinical trial, 2 of 137 ITP patients experienced
hemoglobinemia and/or hemoglobinuria following administration of anti-D
IGIV. The incidence rate of hemoglobinemia and/or hemoglobinuria
associated with anti-D IGIV administration was estimated at 1.5%, with
an estimated incidence of 1 case of hemoglobinemia and/or
hemoglobinuria per 69 ITP patients treated with anti-D IGIV. From the
composite of clinical studies in the literature involving 528 ITP
patients, there were no patients reported to have experienced
hemoglobinemia and/or hemoglobinuria in association with anti-D IGIV
administration, thereby yielding 0 as the estimated incidence rate and
the estimated incidence. Based on FDA and IMS data for the time period
of March 1995 to December 1998, 13 cases of hemoglobinemia and/or
hemoglobinuria following anti-D IGIV administration for the ITP
indication were reported. During that period, an estimated 14 500
patients were treated with anti-D IGIV indication,
corresponding to a 0.1% estimated reporting rate and an estimated
incidence of 1 in 1115.
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Table 2.
Estimated frequency of hemoglobinemia and/or
hemoglobinuria following administration of anti-D IGIV for the ITP
indication
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Discussion |
Case series patients reported to FDA
The extent to which the 15 case series patients were representative
of the population of ITP patients is indeterminate. For the 11 patients
whose presenting diagnosis was ITP, information was generally
unavailable concerning the criteria employed to diagnose ITP and
whether or how differential diagnoses had excluded other hematologic or
medical causes of thrombocytopenia. For the patients whose indication
for treatment with anti-D IGIV was not otherwise specified
thrombocytopenia, the presenting diagnosis was unavailable and may or
may not have been ITP. For patients whose presenting diagnosis may not
have been ITP, for the patient whose indication for use was autoimmune
hemolytic anemia, and for the patient who had previously undergone
splenectomy, the basis on which physicians decided to treat them
off-label with anti-D IGIV was unknown.
Limitations of the above data notwithstanding, the merit of this case
series is that it describes clinical and laboratory findings associated
with acute onset hemoglobinemia and/or hemoglobinuria following
treatment of patients with anti-D IGIV for the ITP indication. Furthermore, the case series notes the occurrence of
treatment-associated sequelae that are not explicitly specified in the
package insert that was current at the time of this review and that
have not been previously reported in the literature (Dr M. Tarantino, personal communication, June
1999).2,4-8,10,11,13,14,23
Had this case series review been a prospective instead of a
retrospective analysis, the case definition would have specified diagnostic criteria for inclusion or exclusion of patients.
Supplemental laboratory data would have been obtained including, among
others, Rh phenotypes, appropriately timed pretreatment and
posttreatment serum hemoglobins, haptoglobins, and complements as well
as DATs, elutions, and IATs. Additionally, ITP patients who did not
experience hemoglobinemia and/or hemoglobinuria following anti-D IGIV
administration would have been included as a control group. Had all
such data been available, multivariate statistical analysis could have
been used to examine for possible relationships between and among
variables for inferences about patients at risk for hemoglobinemia
and/or hemoglobinuria as well as patients at risk for
treatment-associated sequelae.
Frequency of hemoglobinemia and/or hemoglobinuria following
anti-D IGIV administration for the ITP indication
Given the proprietary nature of clinical trial data, the only such
data available for this review were for the subset of 137 patients
published in the literature.6 Whether all patients were
monitored for hemoglobinuria and/or hemoglobinemia or whether it was
only coincidentally observed was not reported. The extent to which the
clinical trial patients were representative of the population of ITP
patients is unknown, given the potential bias that may exist in
clinical trials.20,24 The frequency estimates from the
clinical trial might have differed if calculated from data for the
total sample of 257 clinical trial patients referenced in the package
insert.1
None of the 528 ITP patients in the clinical
studies2,4,7,8,10,11,23 were reported to have experienced
hemoglobinemia and/or hemoglobinuria after treatment. However, from the
information provided, the possibility cannot be excluded that
hemoglobinemia and/or hemoglobinuria occurred but was unrecognized, not
perceived as an adverse event, or did not exceed the threshold
for reporting as an adverse event. Furthermore, the extent to
which the patients were representative of the population of
ITP patients is unknown, as diagnostic criteria for patients were not
generally reported.
There is acknowledged underreporting in passive surveillance adverse
event reporting systems such as the FDA system.20,24 Aside
from this, it is likely that FDA data further underestimated the number
of cases due to the lack of recognition of hemoglobinemia and/or
hemoglobinuria by attending or consulting physicians. This problem
occurred in 5 of the 15 case series patients. In addition, insufficient
data were available to evaluate 6 other possible cases of
hemoglobinemia and/or hemoglobinuria against the case definition.
Although the assumptions used to translate the IMS data into an
estimated number of ITP patients treated with anti-D IGIV were
referenced in the literature to the extent
possible,2,4,7,20,25-27 these assumptions may nonetheless
have been invalid.
Studies or reports involving between 5 and 1842 infusions of anti-D
IGIV and between 20 and 261 ITP patients provided one frame
of reference for evaluating the frequency estimates calculated. In
those studies and reports, the estimated incidence rates for all
adverse events attributed to anti-D IGIV treatment ranged from 1% to
16%.1,2,4,6-8,27 When compared with the magnitude and
marked variability of these estimated incidence rates, the frequency
estimates of 1.5% from the clinical trial and 0.1% from the FDA and
IMS data seem plausible. Although the estimated frequency rates of the
clinical trial and the FDA and IMS data cannot be construed as actual
incidence rates, they provide first approximations against which
physicians may be able to preliminarily assess the risk-benefit ratio
of treating ITP patients with anti-D IGIV.
Between May 1999 and October 1999, subsequent to the time period of
this review, the FDA received an additional 26 anti-D IGIV adverse
event reports of possible or probable hemoglobinemia and/or
hemoglobinuria in ITP patients. Follow-up is in progress to
obtain supplemental data to further evaluate these cases
against the case definition. These additional cases appear to
affirm that hemoglobinemia and/or hemoglobinuria in the case series
patients was not a spurious occurrence. Use of anti-D IGIV for the
treatment of ITP has continued to increase in the United States since
licensure,21,22 which may be attributed to factors such as
efficacy, safety, cost, and
availability.2,4,5,7-9,11,13,14,26-28 Thus, the potential exists for continued occurrence of anti-D IGIV-associated
hemoglobinemia and/or hemoglobinuria and sequelae.
Mechanism(s) of hemoglobinemia and/or hemoglobinuria
following anti-D IGIV administration for the ITP indication
The primary mechanism of action of anti-D IGIV and the temporal
association between anti-D IGIV administration and the onset of
hemoglobinemia and/or hemoglobinuria suggest a causal relationship in
the clinical trial and in the case series patients. However, neither
the literature nor the case series data confirm or rule out this
presumed causality on the basis of established mechanisms of
immune-mediated hemolysis. If attributable to anti-D, the mechanism by
which hemoglobinemia and/or hemoglobinuria occurs is unexplained given
the relatively limited number of D antigens per RBC7,29-31 and the distance between these antigens, which exceeds the span of IgG
anti-D7,30-32; the generally noncomplement-fixing behavior of anti-D2,7,30-33; and the relative lack of complement
activators in anti-D IGIV.4,6,17,18 The literature and case
series data do not definitively indicate whether the hemoglobinemia
and/or hemoglobinuria is attributable to intravascular hemolysis,
extravascular hemolysis, or both.5,12,23,29-31,33
Other mechanisms or explanations could be responsible for
precipitating, accompanying, or potentiating hemoglobinemia and/or hemoglobinuria, although they were not evaluated. Possible mechanisms or explanations include concomitant diagnoses associated with immune-mediated hemolysis, either not reported or not yet diagnosed, such as autoimmune hemolytic anemia and Evan's
syndrome12,29,30; Rh phenotype, which determines the number
of D antigens/RBC29-32 and may influence the degree of
anti-D-mediated hemolysis23,34; splenic saturation and
correspondingly diminished capacity for clearance of anti-D-sensitized
RBCs29,30; concentrations of IgG1,
IgG3, protein aggregates, and/or anti-idiotype antibodies in anti-D IGIV, which may form complement-fixing immune complexes in
vivo (Dr R. Grimes, personal communication, May
1999)4,7,16-18,27,29,30; and conditions of storage and
reconstitution of anti-D IGIV, among others.27
It has been suggested that more than one mechanism may be responsible
for the platelet response of ITP patients treated with anti-D
IGIV.2,4,5,7,10,12,16 Similarly, multiple mechanisms and
explanations may occur or interact to result in hemoglobinemia and/or
hemoglobinuria. Furthermore, different mechanisms or explanations may
account for this occurrence in different patients. Unquestionably, further research and more data are needed to clarify the mechanism(s) or explanation(s) involved.
Implications for treatment of ITP patients with anti-D IGIV for the
ITP indication
The results of this case series suggest that patients treated with
anti-D IGIV for the ITP indication should be closely monitored for
signs and symptoms of hemoglobinemia and/or hemoglobinuria, clinically
compromising anemia, and renal insufficiency. Although no other
sequelae were noted in the clinical trial literature report or in the
patients reported to the FDA, hemoglobinemia and/or hemoglobinuria has
been associated with other clinical complications, notably disseminated
intravascular coagulation,30,32,35 and patients should be
monitored for signs and symptoms of this and other possible sequelae.
When transfusion with PRBCs is indicated in the presence of ongoing
hemoglobinemia and/or hemoglobinuria, physicians may wish to consider
transfusion with D-negative PRBCs.30,32,35 Platelet concentrates as well as apheresis platelets may contain 0.5 to 5.0 mL
of RBCs26,32,35; hence, caution may be appropriate if
platelets from D-positive donors are transfused during
episodes of hemoglobinemia and/or hemoglobinuria.
The FDA encourages physicians and other health care
professionals to report cases of hemoglobinemia and/or
hemoglobinuria following administration of anti-D IGIV for the ITP
indication either to the manufacturer or directly to the FDA. Adverse
events related to anti-D IGIV or any other FDA-licensed or FDA-approved product may be reported to the FDA's adverse event reporting
system, MEDWATCH, by any of the following methods: telephone
(1-800-FDA-1088); fax (1-800-FDA-0178); mail (MEDWATCH, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787); or the Internet
(http://www.fda.gov/medwatch).
| |
Acknowledgments |
The author wishes to thank the physicians and other health care
professionals who reported these adverse events to the FDA and/or
to the manufacturer and whose tireless and repeated reviews of
patients' charts provided the data for this case series.
Unfortunately, due to the many individuals involved, they cannot be
acknowledged individually. The author would also like to express
appreciation to Drs Susan Ellenberg, Marcel Salive, Richard Kapit,
Jerome Donlon, Dorothy Scott, Basil Golding, and Ellen Lazarus from the
Center for Biologics Evaluation and Review, FDA, Rockville, MD, for
their review of this manuscript; to Joslyn Swann and Katrina Garry from the Center for Drug Evaluation and Research, FDA,
Rockville, MD, for providing the raw IMS data and
obtaining its clearance, respectively; and to Karen Cipolone, Karen
Kiekhaefer, and Sharon Moore from the Department of Transfusion
Medicine, National Institutes of Health, Bethesda, MD, for their input.
| |
Footnotes |
Submitted September 15, 1999; accepted December 14, 1999.
Reprints: Ann Reed Gaines, Office of Biostatistics and
Epidemiology, HFM-220, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852;
e-mail: gaines{at}cber.fda.gov.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction