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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 909-913
The Incidence of Idiopathic Thrombocytopenic Purpura in Adults
Increases With Age
By
Henrik Frederiksen and
Kai Schmidt
From the Department of Hematology, Odense University Hospital,
Odense, Denmark.
 |
ABSTRACT |
With the aim of determining the incidence of idiopathic
thrombocytopenic purpura (ITP) in adults, we searched all adult ITP patients diagnosed from April 1, 1973 to December 31, 1995 in the
County of Funen in Denmark. This county comprises 9% of the total
Danish adult population. A total of 221 patients fulfilled the
inclusion criteria, yielding an annual standardized incidence rate of
2.68 per 100,000. The median age of the patient population was 56 years, and the female to male ratio was 1.7. Changing the platelet
count cut-off point from 100 × 109/L to 50 × 109/L changed the incidence rate to 2.25 per 100,000. Comparing patients less and more than 60 years old, the incidence rate
more than doubled and the sex difference was eliminated in the older
age group. These two age groups were almost identical regarding
platelet count at diagnosis and number of asymptomatic cases. The
incidence rate increased in the study period. This increase in
particular involved asymptomatic patients and old males who were both
symptomatic or not symptomatic. Including additional patients
identified by a questionnaire study of the contribution from the
primary care physicians and the practicing specialists in the second
half of the study period, a reliable estimate of the annual ITP
incidence in Danish adults, using a platelet concentration cut-off
point of 50 × 109/L, is 3.2 per 100,000 persons.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
DESPITE THE FACT THAT idiopathic
thrombocytopenic purpura (ITP) is considered a relatively common and
easily recognized disease, no firm data are available on its incidence.
Based on 2 differently structured case studies and 1 quoted estimate of the incidence of childhood ITP, an adult ITP incidence of 6.6 per
100,000 persons per year was estimated by extrapolation from other case
series, including both children and adults.1 Even if it is
the general view that most patients are young women,1 the
impression that the adult ITP population may be older than hitherto
supposed has been expressed previously.2,3 However, there
are no firm data describing the demographic aspects of adult ITP. In an
attempt to address this issue, we have studied all cases of adult ITP
in the well-defined health care region of a Danish county during a
22.75-year period.
| |
MATERIALS AND METHODS |
The background population and the health care system.
In 1984, corresponding to the middle of the study period, the
population of the County of Funen comprised 368,491 inhabitants more
than 15 years of age, corresponding to 8.9% of the analogous total
Danish population. In 1973 and 1995, the numbers were 339,578 and
387,841, respectively, corresponding to 8.8% and 9.0% of the total
Danish population more than 15 years of age. Valid data describing the
mobility of the inhabitants of the County of Funen exist from 1979 and
onwards. In 1979, 1987, and 1995, the fractions of newcomers more than
15 years of age constituted 2.2%, 2.3%, and 2.4%, respectively. The
corresponding fractions of residents leaving the county were 2.2%,
2.2%, and 2.5%, respectively. The health care system of the County of
Funen that takes care of virtually all patients living in its area
consists of one tertiary referral center (Odense University Hospital,
Odense, Denmark) and 9 county hospitals, with a total of 63 out-patient
clinics attached. The number of general practices at the end of the
study period was 183, corresponding to 282 doctors. In addition, the 11 practicing internists and dermatologists of the county were found
relevant for this study.
Searching the records of ITP patients.
We retrieved the records of all ITP patients more than 15 years of age
living in the County of Funen at the time of diagnosis in the
22.75-year period from April 1, 1973 to December 31, 1995. During this
period, all discharge diagnoses in the county were entered into a
computer database. In the out-patient clinics, registration of
diagnoses started at different times from 1978 to 1993; the
hematological out-patient clinic at Odense University Hospital entered
data from 1983.
An initial computer search was conducted applying the following patient
characteristics: (1) residency in the County of Funen at the time of
diagnosis; (2) more than 15 years of age; and (3) characterized by one
or more of the following ICD 8 and ICD 10 classification codes at
discharge (Denmark never used the ICD 9): ICD 8 codes: 287.10 (idiopathic thrombocytopenia), 287.11 (secondary thrombocytopenia);
287.18 (thrombocytopenia, unspecified); 287.19 (thrombocytopenia); and
675.09 (other coagulopathies after childbirth); ICD 10 codes (from
January 1, 1994): D69.3 (idiopathic thrombocytopenic
purpura), D69.4 (other primary thrombocytopenia), D69.5 (secondary
thrombocytopenia), D69.6 (thrombocytopenia, unspecified), and O72.3
(postpartum coagulation defects). The ICD 8 classification code 287.99 (hemorrhagic disease not otherwise specified) corresponding to
unspecific bleeding tendency was included initially. After the
observation that none of 180 patients corresponding to this code
fulfilled the criteria for inclusion, this code and the corresponding ICD 10 code were subsequently omitted.
After a thorough review of the medical records of all patients found by
the intial computer search, patients were included if they had a
platelet count less than 100 × 109/L and did not show
any signs of other hematological disorders, ie, leukemia, lymphoma,
myelodysplastic syndrome, congenital thrombocytopenia, etc. Other
reasons for exclusion were suspected or known chronic hepatic disease
and/or alcohol abuse associated with slight or moderate
thrombocytopenia, solid tumors (both with and without bone marrow
involvement), systemic lupus erythematosus criteria fulfilled at the
appearance of thrombocytopenia, disseminated intravascular coagulation,
thrombotic thrombocytopenic purpura, pseudothrombocytopenia,
drug-induced thrombocytopenia, human immunodeficiency virus
(HIV)-associated thrombocytopenia, and transient gestational thrombocytopenia.
Thrombocytopenic patients who had a previous history of
thrombocytopenia either before 15 years of age or before April 1, 1973 were included if they had a preceding unmaintained normal platelet
count of at least 2 years in duration. A bone marrow examination was
not a prerequisite for inclusion. In patients without a bone marrow
study, at least 6 months of follow-up were required to exclude other
hematological disorders. When performed, the bone marrow study should
show a normal or increased amount of megakaryocytes.
With the purpose of searching ITP patients from the County of Funen
that had been diagnosed in hospitals outside Funen, we also extracted
data from the National Hospital Discharge Registry. This data
extraction, which was based on the previously mentioned criteria and
which covered all Danish hospitals and out-patient clinics outside the
County of Funen, resulted in the inclusion of 1 further patient.
ITP patients diagnosed and treated outside the hospital system.
To get an estimate of the number of ITP patients that had been
diagnosed and observed solely in the primary care system, all general
practitioners, internists, and dermatologists of the county were
questioned as to whether they remembered having diagnosed and possibly
treated ITP patients without referring them within the past 2 years. In
addition, they were asked if they would themselves treat symptomatic
patients outside the hospital system.
Statistics.
Continuous independent variables were analyzed by parametric statistics
(Student's t-test). Normal distribution was confirmed with the
Lilliefors test. Normality was rejected at P < .1. In these
cases, lognormal distribution was tested after logarithmic transformation. In the remaining cases, nonparametric tests
(Mann-Whitney and Kruskal-Wallis) were used. Categorical data were
analyzed using the  2 test with Yates' continuity
correction. Comparison of incidence rates was performed using the
Poisson distribution. A general two-sided significance level of 5% was applied.
Ethics.
The study was approved by The Regional Scientific-Ethical Committee and
by The Danish Data Protection Agency.
| |
RESULTS |
Incidence rates.
Seven hundred sixty-one patients fulfilled our primary inclusion
criteria. Corresponding to these patients, 731 records were available.
Eighteen of the 30 missing records had been destroyed 10 years after
the death of the patients, according to the practice of some
departments. The missing patients did not differ from the remaining
patients regarding age or sex. Only 3 patients, 2 of whom were
excluded, were found by searching hospitals outside the County of
Funen. Altogether, 221 patients fulfilled our ITP criteria. Eleven
patients had a previous history of ITP 2 to 26 years (median, 13 years)
before the present episode. The median age of these patients at the
time of the initial diagnosis was 13 years (range, 3 to 60 years).
The 221 patients comprise 139 women (63%) and 82 men (37%), yielding
a female to male (F/M) ratio of 1.7. The median age of the entire
population is 56.4 years (females, 55.6 years; males, 61.6 years). In
patients more than 60 years of age, the F/M ratio is 1.3; in patients
less than 60 years of age, the F/M ratio is 2.1. This difference is not significant.
The overall ITP incidence rate is 2.64/105/yr (95%
confidence interval [CI], 2.29 to 2.98; women, 3.25 [95% CI, 2.71 to 3.79]; men, 2.00 [95% CI, 1.57 to 2.43]).
Applying these observed rates to the total Danish population, we found
an almost identical age- and sex-standardized overall incidence rate of
2.68/105/yr (95% CI, 2.33 to 3.03; women, 3.28 [95% CI,
2.74 to 3.82]; men, 2.06 [95% CI, 1.62 to 2.50]). The overall
incidence rate of ITP with a platelet count less than 50 × 109/L at diagnosis is 2.25/105/yr (95% CI,
1.92 to 2.57; women, 2.71 [95% CI, 2.22 to 3.20]; men, 1.78 [95%
CI, 1.37 to 2.19]).
Figure 1 displays incidence rates in 3 age
groups. It can be seen that the incidence rate increases with age,
reaching 4.62/105/yr (95% CI, 3.72 to 5.52) in persons
more than 60 years of age and 1.94/105/yr (95% CI, 0.59 to
2.29) in those less than 60 years of age. In addition, the sex
difference is eliminated in individuals more than 60 years of age. It
can further be seen that the modest reduction in incidence rate after
the application of a cut-off point of 50 × 109/L
applies to younger and middle-aged women in particular. Using this
criterion, we found an annual incidence rate of 4.07 (95% CI, 3.22 to
4.92) in persons more than 60 years of age and of 1.61 (95% CI, 1.29 to 1.93) in those less than 60 years of age.
View larger version (22K):
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| Fig 1.
ITP incidence rates according to age and sex. The
horizontal bars correspond to incidence rates using a platelet count
cut-off point of 50 × 109/L.
|
|
Platelet counts and bleeding symptoms.
The median platelet count at diagnosis was 12 × 109/L
(range, 0 to 95 × 109/L). Approximately 45% of the
patients had a platelet count less than 10 × 109/L,
and 85% had a count less than 50 × 109/L. In
patients with very low platelet counts, the difference in incidence
between men and women is almost eliminated. In accordance with this,
the initial median platelet count was 15 × 109/L in
women and 8 × 109/L in men (P = .03). The
corresponding counts in patients less than and more than 60 years of
age were 16 × 109/L (women) and 8 × 109/L (men) and 11 × 109/L (women) and 7 × 109/L (men), respectively. Forty-six (21%)
asymptomatic patients were diagnosed incidentally. Their median
platelet count was 49 × 109/L (range, 3 to 92 × 109/L). In patients less than 60 years of age,
20% were asymptomatic; in patients more than 60 years of age, the
corresponding fraction was 22%. Twenty-five patients (11%)
experienced severe bleeding at diagnosis (10 patients <60 years of
age and 15 patients  60 years of age). Severe mucosal bleeding was
seen in 16 patients (6 patients <60 years of age and 10 patients 60
years of age), with 9 patients showing extensive cutaneous bleeding (3 patients <60 years of age and 6 patients 60 years of age). One
patient less than 60 years of age showed a large intramuscular
hematoma. The 2 age groups did not differ significantly regarding
frequency of severe bleeding (P = .13) or mucosal bleeding per
se (P = .09). The platelet count averaged 5.0 × 109/L in the 10 patients less than 60 years of age and 4.7 × 109/L in the 15 patients 60 years of age. A male
patient who was 86 years of age died from intestinal hemorrhage 10 days
after diagnosis with a platelet count of 12 × 109/L. Additionally, a woman 75 years of age
died 5 months after the diagnosis from intestinal, pleural, and
cerebral hemorrhage after a relapse (platelet count, 5 × 109/L). These fatalities occurred in the period from 1973 to 1974. Inclusion of the latter case yields a difference between the 2 age groups of borderline significance (severe bleeding as a whole: P = .09; severe mucosal bleeding: P = .06). Patients
both less than and greater than 60 years of age were observed for a
median of 26 months. No severe bleeding episodes were seen in 16 patients who had platelet counts persistingly less than 50 × 109/L and who were observed for a median of 24 months. In
the patient group as a whole, 55 have died, with 53 of them dying from
causes other than hemorrhage.
Bone marrow examination.
A bone marrow study was performed in 195 patients (88%). The
proportion of patients who underwent this examination was constant during the period. The median age of the examined patients (57.2 years)
differed significantly from that of the patients not examined (37.6 years; P = .03). The median platelet count at diagnosis was 10 × 109/L and 24 × 109/L in examined
and nonexamined patients, respectively (P = .005). A bone
marrow study was performed in 92% of patients more than 60 years of
age and in 91% of patients with a platelet count less than 50 × 109/L at diagnosis.
Temporal variations.
As shown in Fig 2, the number of patients
increased during the study period. This increase, which started in the
late 1980s, involved patients with high platelet counts in particular.
Accordingly, the median platelet counts at diagnosis were 7 × 109/L, 10 × 109/L, and 16 × 109/L in 1973 to 1980, 1981 to 1987, and 1988 to 1995, respectively. Comparing the incidence rates before and after January 1, 1985 in various groups of patients and using 3 platelet count cut-off points gave the following results (incidence rates are expressed as the
number per 105 persons per year; CIs are not shown). At
less than 100 × 109/L, the values were as follows:
overall before, 1.94, and overall after, 3.33 (P < .0001);
women before, 2.30, and women after, 4.20 (P = .0004); men
before, 1.56, and men after, 2.43 (P = .03); patients less than
60 years of age before, 1.58, and patients less than 60 years of age
after, 2.27 (P = .01); patients 60 years of age
before, 2.94, and patients 60 years of age after, 6.40 (P < .0001). At less than 50 × 109/L, the values were as
follows: overall before, 1.84, and overall after, 2.67 (P = .007); women before, 2.16, and women after, 3.27 (P = .007);
men before, 1.51, and men after, 2.04 (P = .09);
patients less than 60 years of age before, 1.49, and patients less than 60 years of age after, 1.73 (P = .2); patients 60 years of
age before, 2.85, and patients 60 years of age after 5.38 (P < .0001). At less than 20 × 109/L, the values were
as follows: overall before, 1.43, and overall after, 1.86 (P = .07); women before, 1.64, and women after, 2.29 (P = .08); men
before, 1.22, and men after, 1.41 (P = .3); patients less than
60 years of age before, 1.13, and patients less than 60 years of age
after, 1.19 (0.4); patients 60 years of age before, 2.30, and
patients 60 years of age after, 3.80 (P < .0001). The increasing number of patients applies to women of all ages and to old
men. Accordingly, the age of the male patients changed from a median of
35.1 years in 1973 to 1980 to 45.8 years in 1981 to 1987 and 65.6 years
in 1988 to 1995 (P = .01). The corresponding figures for women
are 55.6, 55.6, and 54.2 years, respectively (P = .9). In
symptomatic male patients, the median ages in the 3 periods were 33.3, 47.7, and 65.3 years, respectively (P = .01).
In accordance with the finding of increasing platelet counts, the
number of asymptomatic patients increased in the study period. The
incidence rates of symptomatic ITP before and after January 1, 1985 were 1.82/105/yr and 2.36/105/yr, respectively
(P = .05). The corresponding incidence rates of asymptomatic
patients were 0.12/105/yr and 0.98/105/yr
(P < .0001).
Referral pattern.
The number of in-patients and out-patients was 196 and 25, respectively. Twenty-four of the 25 out-patients were seen in the specialized department. Twenty-two of these (92%) were seen from 1990 to 1995, ie, in the latter half of this department's computerized out-patient data entry period.
The questionnaires forwarded to the general practitioners and
practicing specialists resulted in a 94% response rate. From the
answers it can be estimated that 2 ITP patients with platelet counts
less than 50 × 109/L and 6 patients with platelet
counts between 50 × 109/L and 100 × 109/L were diagnosed annually outside the hospital system
in the County of Funen. It can also be concluded that presumably all symptomatic ITP patients would be referred to the hospital system. Provided that these estimates are valid, they result in an increase in
the overall ITP incidence rate from 2.64/105/yr to
4.81/105/yr (95% CI, 4.34 to 5.28). If only platelet
counts less than 50 × 109/L at diagnosis are
considered, the incidence rate increases from 2.25/105/yr
to 2.80/105/yr (95% CI, 2.44 to 3.16) in the study period
as a whole and from 2.67 to 3.22 in the period from 1985 to 1995.
| |
DISCUSSION |
The fact that ITP remains a diagnosis of exclusion has made study of
its epidemiologic and demographic aspects difficult. Consequently, firm
data on its incidence are not available. Based on a literature review,
George et al1 estimated an annual ITP incidence rate of 1.0 to 12.5 per 100,000 persons (children and adults). All investigators
agree that there is a female preponderance, with an estimated F/M ratio
of 2.6:1,1 and it is a general belief that ITP is typically
a disease of young adults, with a peak of occurrence between 15 and 40 years of age and a decreasing rate of incidence with age.
In the present study, we have made a careful search for all adult ITP
patients diagnosed during a 22.75-year period in a well-defined Danish
health care region with a stable, representative population. Using a
platelet concentration cut-off point of 100 × 109/L,
we found an annual incidence rate of 2.64 per 100,000 persons. Considering only platelet counts less than 50 × 109/L, the incidence rate decreased to 2.25 per 100,000 persons. Our F/M ratio is 1.7, which is somewhat lower than that
reported in previously published series.1 Besides, a
remarkable and rather surprising finding is the median age of 56 years
of our patient population. We found an increasing annual ITP incidence with age, reaching 4.6 per 100,000 persons more than 60 years of age.
Furthermore, the sex difference was eliminated in this older group of
patients. The validity of our finding is supported by the fact that the
older patients did not differ from their younger counterparts as
regards platelet concentration at diagnosis. Accordingly, lowering the
platelet concentration threshold to 50 × 109/L and
excluding asymptomatic patients does not affect our results. Considering the estimated low number of patients treated in the primary
health care system, it is unlikely that the age composition of the
patients is affected by referral bias. The high frequency of bone
marrow examination, particularly in the older patients, makes erroneous
inclusion of patients with myelodysplastic syndromes very unlikely.
Accordingly, no ITP patient from the study period has so far been seen
in the region's specialized department of hematology with a subsequent
diagnosis of myelodysplasia. It is also unlikely that drug-induced
thrombocytopenia contributes to the high ITP incidence in the older
patients, because the administration of candidate drugs was stopped in
almost all patients.
It is of interest that an increased incidence with age has previously
been described in hemolytic anemia4 and quite recently in
systemic lupus erythematosus as well.5
Almost half of our patients are more than 60 years of age. Two
patients, 75 and 86 years of age, died from excessive bleeding. Apart
from this, it is remarkable that old and young patients with comparable
platelet counts at diagnosis and subsequent follow-up periods seemed to
show the same severity of bleeding. Even if we found a trend towards
more cases of severe bleeding in the older age group, our results
contrast with previous studies that have shown an increased risk of
severe bleeding in aged patients with ITP.6,7 Selection
bias and a rather low number of old patients in these studies may
contribute to this discrepancy.
The temporal variation in the incidence pattern deserves special
consideration. The annual incidence rate increased from 1.94 to 3.33 per 100,000 persons in the halves of the study period. A somewhat less
pronounced increase, from 1.84 to 2.67, was seen if the 50 × 109/L platelet count criterion was applied. Accordingly,
the number of asymptomatic patients increased considerably with time.
Presumably, this can be ascribed to incidental finding of slightly
lowered platelet counts during routinely performed platelet counting
after the introduction of automated platelet counting.
It is remarkable that the conspicuously increased ITP incidence of
older patients with time involved males in particular. This increase,
the cause of which is not known, must be real in view of the fact that
this trend was also found in symptomatic male patients.
It is likely that the vast majority of symptomatic patients are
referred, ie, patients with platelet counts less than 50 × 109/L.8 Considering the ITP incidence in the
second half of our study period and the result of our questionnaire
study of the contribution from the primary care physicians, a realistic
estimate of the annual ITP incidence in Danish adults, using a platelet concentration cut-off point of 50 × 109/L, is
3.2 per 100,000 persons. The corresponding estimate of 5.5 per 100,000 per year using a 100 × 109/L threshhold is subject to
some uncertainty because of the lack of precise knowledge of the exact
number of patients observed exclusively in the primary health care
system and (not least) because of the unknown number of patients with
asymptomatic ITP.
| |
FOOTNOTES |
Submitted November 17, 1998; accepted April 13, 1999.
Supported by grants from the Dagmar Marshall's Foundation, Denmark;
the Family Hede Nielsen's Foundation, Denmark; and the Asta og Peter
Gøtz-Petersen's Foundation, Denmark.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Kai Schmidt, MD, Department of
Hematology, Odense University Hospital, DK-5000 Odense C, Denmark.
| |
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Ann Intern Med,
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J. E. A. Portielje, R. G. J. Westendorp, H. C. Kluin-Nelemans, and A. Brand
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TOP
ABSTRACT
INTRODUCTION
