Örebro University School of Medicine Degree Project, 15 ECTS June 2017 Characteristics, treatment and outcome of warm autoimmune hemolytic anemia Version 2 Author: Rickard Hedberg Supervisor: Bertil Uggla, MD, PhD Örebro, Sweden
Characteristics, treatment and outcome of warm autoimmune hemolytic anemia
Jan 15, 2023
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Örebro University School of Medicine Degree Project, 15 ECTS June 2017
Characteristics, treatment and outcome of warm autoimmune hemolytic anemia
Version 2
Örebro, Sweden
Warm autoimmune hemolytic anemia (wAIHA) is an acquired, rare autoimmune hemolytic
disease in which antibodies are created against the erythrocytes produced by the body.
Aim
In order to create an overview of characteristics, adherence to guidelines regarding treatment
and frequency of remission, this study was conducted.
Methods
This study is a single-center retrospective study of patients who received the diagnosis of
wAIHA at the Division of Hematology, Department of Medicine, Örebro University Hospital,
Örebro, between 2006 and 2015. The study included data from both patient journals and
laboratory test results. Patient characteristics and adherence to guidelines regarding treatment
were studied by documenting the treatment given for wAIHA.
Results
Fifty patients (19 females, 31 males) were included; the mean age at time of diagnosis was 67
± 16 years. Twenty-nine patients were considered having primary wAIHA. The remaining 21
patients were considered having secondary wAIHA, 15 of which had wAIHA secondary to
chronic lymphocytic leukemia (CLL). Every patient except for three needed and received
treatment with corticosteroids. 87 % of patients who received corticosteroids responded to
corticosteroids by reaching either complete remission (CR) or partial remission (PR). 14 (30
%) of those who received first line treatment, received at least one second line treatment, 11 of
which received rituximab.
Adherence to guidelines regarding first line treatment and second line treatments were higher
than adherence regarding for folic acid supplementation, calcium-D-vitamin supplements,
bisphosphonates and specific thromboprophylaxis.
Rickard Hedberg Page 3
Background
Autoimmune hemolytic anemia (AIHA) is a form of acquired hemolytic anemia in which the
host’s immune system gives rise to autoantibodies that target the host’s erythrocytes [1-2].
AIHA is serologically divided into warm autoimmune hemolytic anemia (wAIHA), that make
up 65 % of cases, and cold autoimmune hemolytic anemia, which accounts for 30 % of cases.
There is as well a mixed type that accounts for 5 % of cases [1]. AIHA can be either primary
or secondary to an underlying disorder, which may be malignancy (often CLL), infection or
another autoimmune disease. AIHA can arise in both adults and children, among children most
commonly before the age of 5. The estimated annual incidence of AIHA among Caucasians is
1-3 per 100 000 individuals with a rising incidence with increasing age [1-3].
The hemolysis initiates with erythrocytes being opsonized by the autoantibody. The degree of
hemolysis is determined by antibody related factors such as: its ability to bind to tissue
macrophages, its ability to fix complement factors, quantity of antibodies, the specificity of the
antibodies, its thermal amplitude. Other factors include density and expression of the antigen
as well as the age of the patient [2].
Patients with AIHA can exhibit symptoms of anemia (dizziness 50 %, dyspnea 9 % and fatigue
88 %), chest pain and hemolysis (dark urine 3 %, jaundice 21 %) as well as symptoms of
underlying disorders [2-3]. Symptoms may have an insidious onset which may be subacute or
acute [4]. An increased risk for venous thrombosis in patients with wAIHA has been described
[5].
Therapy for remission induction is necessary for most patients with AIHA. In cases with
wAIHA, glucocorticoids with or without supplementary high dose immunoglobulins remain
the first line therapy. A common second line therapy is splenectomy. Primary wAIHA has a
high response rate to corticosteroid therapy. Rituximab (anti-CD20) is another
immunosuppressive treatment that has emerged as a preferred second line treatment as it has
proved to be very effective in patients with secondary wAIHA that came to be refractory to first
line therapy [3, 4, 6, 7]. The response rate of rituximab is approximately 60 % [6].
Besides from remission-inducing treatments, such as corticosteroids, rituximab and
immunoglobulins, there are often a need for supplementing with treatment of the anemia itself.
In cases of severe anemia blood transfusion is necessary [8].
Rickard Hedberg Page 4
An elevated risk of venous thrombosis is a significant cause of morbidity and mortality among
patients with wAIHA, the greater the hemolysis is, the greater the risk of thrombosis is found
to be. Two studies have found that in patients with severe AIHA (defined as Hb less than 85
g/l), venous thrombosis occurred in 20-21 % of all cases, in patients without
thromboprophylaxis as many as one of three had thrombosis, in patients with
thromboprophylaxis as few as one of 21 had thrombosis [5, 9].
The use of folic acid supplementation has reduced the amount of cases of folic acid deficiency
and megaloblastic anemia in patients with chronic hemolysis [1].
Long term (≥ 3 months) treatment with glucocorticoids has been found to cause osteoporotic
fractures in up to 30-50 % [10]. In order to counteract the osteoporosis-inducing effect of long
term treatment with glucocorticoids, calcium and vitamin D supplements are recommended for
all patients receiving glucocorticoids [10-11]. Bone mineral density has been found to be
increased by bisphosphonates and is therefore along with calcium and vitamin D supplements
recommended for postmenopausal women and men above 50 years age who receive long term
treatment with glucocorticoids [12-14].
The purpose of this study is to make a single-center retrospective study of diagnostics, treatment
and complications regarding patients with a first episode of AIHA at the Section for
Hematology at USÖ. In Sweden, there are no national guidelines for wAIHA, instead British
guidelines (British Society for Haematology, 2016) will be used.
Key abbreviations: CLL = Chronic Lymphocytic Leukemia. DAT = Direct Antiglobulin Test.
IViG = IntraVenous ImmunoGlobulin. LD = Lactate Dehydrogenase. Remission = a state in a
chronic disease in which the symptoms partially or completely are absent. wAIHA = warm
AutoImmune Hemolytic Anemia. WBC = White blood cell count.
Rickard Hedberg Page 5
Methods
This study was a single-center retrospective cohort study conducted at the Örebro University
Hospital (Örebro, Sweden).
1. The patient received a definite diagnosis of wAIHA.
2. The diagnosis and treatment occurred at the Division of Hematology, Department of
Medicine, Örebro University Hospital between January 1st 2006 and December 31st
2015.
3. The patients had a positive DAT-pattern with an isolated IgG, isolated C3d or IgG +
C3d pattern.
In order to study the state in which the patients were at the time diagnosis as well as the severity
of their state, several blood levels as well as other data was included. The type of data that was
included and the reason for inclusion will be presented below.
Presence of blood malignancies is a common cause to secondary wAIHA, therefore this was
important to find in order to determine whether the patient had primary or secondary wAIHA
[4].
Presence of other autoimmune diseases is another cause to secondary wAIHA, for the same
reason as above this data was included [4].
Hb level is very important in order to detect anemia and determine its severity as well as the
efficacy of treatment and whether or not the patient achieves complete or partial remission [2-
4].
Bilirubin will typically be increased in cases of hemolysis since unconjugated bilirubin is a rest
product from destroyed erythrocytes. If bilirubin levels are above 50 μmol/l it will give rise to
prehepatic icterus that can be seen by a yellow color in the sclera [1, 4, 15].
LD (Lactate dehydrogenase) is an enzyme that is set free in when damage is made to the heart,
liver, skeletal muscles and erythrocytes. In cases of hemolysis LD may be either normal or
elevated [1, 4, 16].
Haptoglobin binds to free hemoglobin and is thereby consumed, therefore haptoglobin is a
marker for hemolysis that in case of hemolysis usually become reduced [1, 4, 17].
Rickard Hedberg Page 6
Reticulocyte count is elevated in cases of hemolysis since the increased loss of mature
erythrocytes is being compensated by an increased production of new ones, which gives rise to
higher count of immature erythrocytes called reticulocytes [1, 4, 18].
WBC (White blood cell count) may be elevated as a result of malignancy, however, there are
many other conditions in which WBC may be elevated, such as infection or inflammatory
disorders [19].
Platelet level, which if elevated is linked to increased risk of thrombosis [20].
In order to tell whether the hemolysis is autoimmune a direct antiglobulin test (DAT) is made,
a positive result indicates an existence of autoreactive immunoglobulin IgA, IgG, IgM or
complement (commonly C3d) that is bound to the erythrocytes cell membrane. If the patient
has a positive DAT for either IgG or IgG + C3d, the test indicates that the patient has wAIHA
[1-4].
A positive DAT result does not necessary mean that the patient has AIHA, since the test is not
entirely specific. A positive DAT may occur in many non-hemolytic diseases, such as chronic
infection, liver disease, malignancy and SLE [1].
There are however patients who have AIHA and a negative DAT, some may have a false
negative DAT, others have a false negative due to treatment with immunoglobulins, etc. Only
DAT positive patients were included in the study [1-4].
Need for transfusion is an important way of telling the percentage of patients who had a severe
enough anemia during their disease progression to receive transfusion.
Number of units transfused is a further way of telling the severity of the disease.
Complete and partial remission was used to assess treatment efficacy. Complete remission was
defined as an Hb ≥ 120 g/l. Partial remission was defined as an Hb ≥ 100 g/l with an increase
of ≥ 20 g/l from Hb at diagnosis.
First, second, third and fourth line treatment was included in order to describe the percentage
who needed different treatment lines as well as different treatments.
Time until second treatment line was of interest in order to measure the time it took until the
need to complement the first line treatment with a second line treatment arose.
Rickard Hedberg Page 7
Patients with corticosteroids were measured as the amount and percentage of the study
population who received corticosteroids. It is included in order to tell how many patients who
received the recommended first line treatment.
Corticosteroid response was defined as the amount and percentage of the study population who
received corticosteroids and had a complete or partial remission.
Patients with folic acid treatment, calcium-D-vitamin treatment, bisphosphonate treatment and
thromboprophylaxis treatment are being assessed in order to tell how many patients who
received these treatments according to recommendations.
Descriptive statistics comprised mean ± SD for quota variables where 1 SD < mean, median
(range) was used for quota variables in cases where 1 SD > mean. Frequency (amount and
percentage) was used to describe nominal variables such as DAT pattern. Frequency was also
used to describe variables otherwise considered quota variables that given uncertainty of
measurement was better described in frequencies, such as haptoglobin, which in most cases was
measured as <0.1 g/l. Fisher exact test or Chi2 test was used to retrieve P values when
comparing two nominal variables. Fisher exact test was used if at least one cell contained less
than 5 observations. Chi2 test was used if all cells contain at least 5 observations each. Unpaired
T test was used to retrieve P values when comparing one nominal variable with one quota
variable, for example unpaired T test was used to retrieve P value when comparing Hb levels
between patients with primary and secondary wAIHA. All observations were unpaired,
therefore was unpaired and not paired T test used. Differences were considered of significance
at P < 0.05.
Ethics
This study has been conducted as a part of regularly quality assessment at the Division of
Hematology, Department of Medicine, Örebro University Hospital, however it was conducted
in agreement with the ethical standards of the Helsinki Declaration.
This study comprises a thorough review of patients’ journals and laboratory tests. The large
amount of patients combined with the fact that single cases are not depicted in detail, means
that is highly unlikely, if not impossible, to identify any single patient from this report.
Furthermore, any information given about patients in the study population will be presented in
a manner that obstructs recognition of single patients.
Rickard Hedberg Page 8
Aim
The purpose of this study was to create an overview of baseline characteristics and treatment
of patients with wAIHA at USÖ and to assess whether the patients are treated in accordance
with British guidelines (British Society for Haematology, 2016).
Rickard Hedberg Page 9
Patient characteristics at diagnosis
Fifty patients (19 females and 31 males), who fulfilled the inclusion criteria were included in
this study. 29 patients had primary wAIHA,
the remaining 21 patients had secondary
wAIHA.
15.8 years (range 25-88 years). Figure 1
displays the amount of patients in different
age groups at the time of diagnosis.
The mean Hb level for the entire study population at the time of diagnosis was 75.9 ± 21.9 g/l
(reference: 117-153 g/l (F), 134-170 g/l (M)).
Reticulocyte count was at diagnosis measured in 28/29 with primary wAIHA and in 20/21 with
secondary wAIHA. Reticulocyte count was 172.7 ± 131.1 109/l (ref: 30-105 109/l) in the study
population, 67 % had a reticulocyte count above reference interval.
Haptoglobin was measured in all patients except for one patient with primary wAIHA.
Haptoglobin level below reference interval was measured in 84 % of the study population. A
bilirubin level above reference interval was measured in 64 % of the study population.
DAT showed an IgG + C3 pattern in 60 % of cases and an isolated IgG pattern in 40 % of cases.
WBC above reference interval was found in 22 (44 %) of cases. Mean platelet count was found
to be 218 ± 114 109/l (ref: 165-387 (F), 145-348 (M)). Mean LD was 7.3 ± 4.0 μkat/l (ref: < 3.5
μkat/l).
Secondary wAIHA
The most common cause of secondary wAIHA in the study population was chronic lymphocytic
leukemia (CLL), 15 of 21 (71 %) cases.
Other causes included myeloproliferative disorder (n = 1), monoclonal gammopathy of
undetermined significance (n = 1), myeloma (n = 1), myelodysplastic syndrome (n = 1), splenic
lymphoma with villous lymphocytes (n = 1) and autoimmune hepatitis (n = 1).
0
5
10
15
20
25
Figure 1. Amount of patients per age group at diagnosis.
Rickard Hedberg Page 10
least once because of severe anemia. Mean Hb levels (±
1 SD) at diagnosis among patients who received
transfusion was 64.5 ± 18.4 g/l. Of those who received
transfusions, 18 (82 %) received less than 10 erythrocyte
units in total. The remaining four patients received 11, 13,
20 and 43 units of erythrocytes. Patients received a median of 4.5 units erythrocytes.
First line treatment
In all, 47/50 (94 %) patients received the recommended first line treatment of corticosteroids
(prednisolone and/or deltisone), while two patients with primary and one patient with secondary
wAIHA were observed instead of receiving first line treatment since their conditions were mild
and did not have any mentionable impact on their everyday life.
Of the 47 patients who received corticosteroids, the response was possible to determine in 46
patients. One patient had a mild condition with Hb above 100 g/l at diagnosis and Hb rarely
measured thereafter, making it not possible to determine whether the patient achieved complete
remission. In 40/46 patients (87 %) complete remission or partial remission was achieved. Of
these 40 patients, 34 (85 %) achieved complete remission. Twenty of 46 patients (43 %)
achieved complete or partial remission within day 21.
Second line treatment
Of the 47 patients who received first line treatment, 14 (30 %)
received at least one second line treatment, at a median of 21 days
after starting corticosteroid therapy.
Figure 2. Number of Units Erythrocytes Transfused.
Units Transfused
Rickard Hedberg Page 11
Rickard Hedberg Page 12
Rituximab. 11 of 50 (22 %) received at least one course of rituximab. Of the eleven patients
who received rituximab, 5 (45 %) had primary wAIHA and 6 (55 %) had secondary wAIHA.
Splenectomy. 2 of 50 (4 %) patients underwent splenectomy. One of which had a splenectomy
after treatment with corticosteroids and IViG had a poor effect on the hemolysis caused by its
primary wAIHA.
IViG. 3 of 50 (6 %) patients received treatment with IViG after 7, 10 and 11 days after start of
corticosteroid therapy. One of the patients who received IViG treatment afterwards was treated
with rituximab. The second patient only received IViG as second treatment line and achieved
neither partial nor complete remission. The third patient with IViG was reported to have a poor
response to both corticosteroids and IViG.
Other treatments. Other treatments included folic acid, calcium-D-vitamin, bisphosphonates
and thromboprophylaxis. Folic acid treatment was given to 26 of 50 patients (52 %) at any time
after diagnosis. Calcium-D-vitamin treatment was given to 20 of 50 patients (40 %) at any time
after diagnosis.
Bisphosphonate treatment was given to four patients at any time after diagnosis. One patient (4
%) of the 23 patients in the age group ≥70 years received bisphosphonates and three patients
(16 %) of the 19 patients in the age group 50-69 years received bisphosphonates. None received
specific thromboprophylaxis, while 20 patients received anticoagulants due to other conditions.
Rickard Hedberg Page 13
Comparison of primary and secondary cases
Table I compares the main characteristics of patients with primary and secondary wAIHA. At
the time of diagnosis, the biological characteristics did not differ, except for in the frequency
of increased bilirubin level (P = 0.04) and the frequency of increased WBC (P = 0.03). Bilirubin
levels were increased in 22 (76 %) of primary cases and in 10 (48 %) of secondary cases. WBC
was increased in 9 (31 %) of primary cases and 13 (62 %) of secondary cases.
Differences in DAT pattern between the two groups was found to be of significance (P = 0.047).
In the group with primary wAIHA an isolated IgG pattern was found in 15 of 29 (52 %) and an
IgG + C3 pattern in 14 of 29 (48 %), whereas in the group with secondary wAIHA 5 of 21 (24
%) had an isolated IgG pattern and the remaining 16 of 21 (76 %) was found to have an IgG +
C3 pattern. One patient with wAIHA secondary to CLL who did not receive corticosteroids
achieved a spontaneous complete remission. 13 primary and 7 secondary cases received
anticoagulants prior to diagnosis due to pre-existing conditions. TABLE I. Main Characterstics of Patients with Primary and Secondary wAIHA.
Characteristics Primary wAIHA Secondary wAIHA P value Amount of patients 29 21 Mean age at diagnosis (years) 66.1 ± 18.6 68.8 ± 11.1 0.56 Sex ratio (Females/Males) 14 / 15 5 / 16 0.08 Biological characteristics at diagnosis Mean Hb (g/L) Reference: 117-153 g/L (F), 134-170 g/L (M)
77.7 ± 17.4 72.2 ± 22 0.34
High WBC n (%) Reference: 3.5-8.8 x109/L
9 (31 %) 13 (62 %) 0.03
Mean Platelet count (109/L) Reference: 165-387 x109/L (F), 145-348 x109/L (M)
228.8 ± 127.4 202.3 ± 92.9 0.42
Mean Reticulocyte count (109/L) Reference: 30-105 x109/L
194 ± 139.5 143 ± 109.9 0.18
High Reticulocytes n (%) 21 (75 %) 11 (55 %) 0.15 Low Haptoglobin n (%) 26 (93 %) 15 (71 %) 0.06 Elevated Bilirubin level n (%) 22 (76 %) 10 (48 %) 0.04 LD Reference: < 3.5 μkat/L
7.6 ± 4.3 7.0 ± 3.8 0.59
DAT pattern IgG n (%) 15 (52 %) 5 (24 %) 0.047 IgG + C3 n (%) 14 (48 %) 16 (76 %) 0.047 C3 n (%) 0 (0 %) 0 (0 %) Treatment Need for transfusion n (%) 12 (41 %) 10 (48 %) 0.79 Patients with corticosteroids n (%) 27 (93 %) 20 (95 %) 1 Corticosteroid response…
Characteristics, treatment and outcome of warm autoimmune hemolytic anemia
Version 2
Örebro, Sweden
Warm autoimmune hemolytic anemia (wAIHA) is an acquired, rare autoimmune hemolytic
disease in which antibodies are created against the erythrocytes produced by the body.
Aim
In order to create an overview of characteristics, adherence to guidelines regarding treatment
and frequency of remission, this study was conducted.
Methods
This study is a single-center retrospective study of patients who received the diagnosis of
wAIHA at the Division of Hematology, Department of Medicine, Örebro University Hospital,
Örebro, between 2006 and 2015. The study included data from both patient journals and
laboratory test results. Patient characteristics and adherence to guidelines regarding treatment
were studied by documenting the treatment given for wAIHA.
Results
Fifty patients (19 females, 31 males) were included; the mean age at time of diagnosis was 67
± 16 years. Twenty-nine patients were considered having primary wAIHA. The remaining 21
patients were considered having secondary wAIHA, 15 of which had wAIHA secondary to
chronic lymphocytic leukemia (CLL). Every patient except for three needed and received
treatment with corticosteroids. 87 % of patients who received corticosteroids responded to
corticosteroids by reaching either complete remission (CR) or partial remission (PR). 14 (30
%) of those who received first line treatment, received at least one second line treatment, 11 of
which received rituximab.
Adherence to guidelines regarding first line treatment and second line treatments were higher
than adherence regarding for folic acid supplementation, calcium-D-vitamin supplements,
bisphosphonates and specific thromboprophylaxis.
Rickard Hedberg Page 3
Background
Autoimmune hemolytic anemia (AIHA) is a form of acquired hemolytic anemia in which the
host’s immune system gives rise to autoantibodies that target the host’s erythrocytes [1-2].
AIHA is serologically divided into warm autoimmune hemolytic anemia (wAIHA), that make
up 65 % of cases, and cold autoimmune hemolytic anemia, which accounts for 30 % of cases.
There is as well a mixed type that accounts for 5 % of cases [1]. AIHA can be either primary
or secondary to an underlying disorder, which may be malignancy (often CLL), infection or
another autoimmune disease. AIHA can arise in both adults and children, among children most
commonly before the age of 5. The estimated annual incidence of AIHA among Caucasians is
1-3 per 100 000 individuals with a rising incidence with increasing age [1-3].
The hemolysis initiates with erythrocytes being opsonized by the autoantibody. The degree of
hemolysis is determined by antibody related factors such as: its ability to bind to tissue
macrophages, its ability to fix complement factors, quantity of antibodies, the specificity of the
antibodies, its thermal amplitude. Other factors include density and expression of the antigen
as well as the age of the patient [2].
Patients with AIHA can exhibit symptoms of anemia (dizziness 50 %, dyspnea 9 % and fatigue
88 %), chest pain and hemolysis (dark urine 3 %, jaundice 21 %) as well as symptoms of
underlying disorders [2-3]. Symptoms may have an insidious onset which may be subacute or
acute [4]. An increased risk for venous thrombosis in patients with wAIHA has been described
[5].
Therapy for remission induction is necessary for most patients with AIHA. In cases with
wAIHA, glucocorticoids with or without supplementary high dose immunoglobulins remain
the first line therapy. A common second line therapy is splenectomy. Primary wAIHA has a
high response rate to corticosteroid therapy. Rituximab (anti-CD20) is another
immunosuppressive treatment that has emerged as a preferred second line treatment as it has
proved to be very effective in patients with secondary wAIHA that came to be refractory to first
line therapy [3, 4, 6, 7]. The response rate of rituximab is approximately 60 % [6].
Besides from remission-inducing treatments, such as corticosteroids, rituximab and
immunoglobulins, there are often a need for supplementing with treatment of the anemia itself.
In cases of severe anemia blood transfusion is necessary [8].
Rickard Hedberg Page 4
An elevated risk of venous thrombosis is a significant cause of morbidity and mortality among
patients with wAIHA, the greater the hemolysis is, the greater the risk of thrombosis is found
to be. Two studies have found that in patients with severe AIHA (defined as Hb less than 85
g/l), venous thrombosis occurred in 20-21 % of all cases, in patients without
thromboprophylaxis as many as one of three had thrombosis, in patients with
thromboprophylaxis as few as one of 21 had thrombosis [5, 9].
The use of folic acid supplementation has reduced the amount of cases of folic acid deficiency
and megaloblastic anemia in patients with chronic hemolysis [1].
Long term (≥ 3 months) treatment with glucocorticoids has been found to cause osteoporotic
fractures in up to 30-50 % [10]. In order to counteract the osteoporosis-inducing effect of long
term treatment with glucocorticoids, calcium and vitamin D supplements are recommended for
all patients receiving glucocorticoids [10-11]. Bone mineral density has been found to be
increased by bisphosphonates and is therefore along with calcium and vitamin D supplements
recommended for postmenopausal women and men above 50 years age who receive long term
treatment with glucocorticoids [12-14].
The purpose of this study is to make a single-center retrospective study of diagnostics, treatment
and complications regarding patients with a first episode of AIHA at the Section for
Hematology at USÖ. In Sweden, there are no national guidelines for wAIHA, instead British
guidelines (British Society for Haematology, 2016) will be used.
Key abbreviations: CLL = Chronic Lymphocytic Leukemia. DAT = Direct Antiglobulin Test.
IViG = IntraVenous ImmunoGlobulin. LD = Lactate Dehydrogenase. Remission = a state in a
chronic disease in which the symptoms partially or completely are absent. wAIHA = warm
AutoImmune Hemolytic Anemia. WBC = White blood cell count.
Rickard Hedberg Page 5
Methods
This study was a single-center retrospective cohort study conducted at the Örebro University
Hospital (Örebro, Sweden).
1. The patient received a definite diagnosis of wAIHA.
2. The diagnosis and treatment occurred at the Division of Hematology, Department of
Medicine, Örebro University Hospital between January 1st 2006 and December 31st
2015.
3. The patients had a positive DAT-pattern with an isolated IgG, isolated C3d or IgG +
C3d pattern.
In order to study the state in which the patients were at the time diagnosis as well as the severity
of their state, several blood levels as well as other data was included. The type of data that was
included and the reason for inclusion will be presented below.
Presence of blood malignancies is a common cause to secondary wAIHA, therefore this was
important to find in order to determine whether the patient had primary or secondary wAIHA
[4].
Presence of other autoimmune diseases is another cause to secondary wAIHA, for the same
reason as above this data was included [4].
Hb level is very important in order to detect anemia and determine its severity as well as the
efficacy of treatment and whether or not the patient achieves complete or partial remission [2-
4].
Bilirubin will typically be increased in cases of hemolysis since unconjugated bilirubin is a rest
product from destroyed erythrocytes. If bilirubin levels are above 50 μmol/l it will give rise to
prehepatic icterus that can be seen by a yellow color in the sclera [1, 4, 15].
LD (Lactate dehydrogenase) is an enzyme that is set free in when damage is made to the heart,
liver, skeletal muscles and erythrocytes. In cases of hemolysis LD may be either normal or
elevated [1, 4, 16].
Haptoglobin binds to free hemoglobin and is thereby consumed, therefore haptoglobin is a
marker for hemolysis that in case of hemolysis usually become reduced [1, 4, 17].
Rickard Hedberg Page 6
Reticulocyte count is elevated in cases of hemolysis since the increased loss of mature
erythrocytes is being compensated by an increased production of new ones, which gives rise to
higher count of immature erythrocytes called reticulocytes [1, 4, 18].
WBC (White blood cell count) may be elevated as a result of malignancy, however, there are
many other conditions in which WBC may be elevated, such as infection or inflammatory
disorders [19].
Platelet level, which if elevated is linked to increased risk of thrombosis [20].
In order to tell whether the hemolysis is autoimmune a direct antiglobulin test (DAT) is made,
a positive result indicates an existence of autoreactive immunoglobulin IgA, IgG, IgM or
complement (commonly C3d) that is bound to the erythrocytes cell membrane. If the patient
has a positive DAT for either IgG or IgG + C3d, the test indicates that the patient has wAIHA
[1-4].
A positive DAT result does not necessary mean that the patient has AIHA, since the test is not
entirely specific. A positive DAT may occur in many non-hemolytic diseases, such as chronic
infection, liver disease, malignancy and SLE [1].
There are however patients who have AIHA and a negative DAT, some may have a false
negative DAT, others have a false negative due to treatment with immunoglobulins, etc. Only
DAT positive patients were included in the study [1-4].
Need for transfusion is an important way of telling the percentage of patients who had a severe
enough anemia during their disease progression to receive transfusion.
Number of units transfused is a further way of telling the severity of the disease.
Complete and partial remission was used to assess treatment efficacy. Complete remission was
defined as an Hb ≥ 120 g/l. Partial remission was defined as an Hb ≥ 100 g/l with an increase
of ≥ 20 g/l from Hb at diagnosis.
First, second, third and fourth line treatment was included in order to describe the percentage
who needed different treatment lines as well as different treatments.
Time until second treatment line was of interest in order to measure the time it took until the
need to complement the first line treatment with a second line treatment arose.
Rickard Hedberg Page 7
Patients with corticosteroids were measured as the amount and percentage of the study
population who received corticosteroids. It is included in order to tell how many patients who
received the recommended first line treatment.
Corticosteroid response was defined as the amount and percentage of the study population who
received corticosteroids and had a complete or partial remission.
Patients with folic acid treatment, calcium-D-vitamin treatment, bisphosphonate treatment and
thromboprophylaxis treatment are being assessed in order to tell how many patients who
received these treatments according to recommendations.
Descriptive statistics comprised mean ± SD for quota variables where 1 SD < mean, median
(range) was used for quota variables in cases where 1 SD > mean. Frequency (amount and
percentage) was used to describe nominal variables such as DAT pattern. Frequency was also
used to describe variables otherwise considered quota variables that given uncertainty of
measurement was better described in frequencies, such as haptoglobin, which in most cases was
measured as <0.1 g/l. Fisher exact test or Chi2 test was used to retrieve P values when
comparing two nominal variables. Fisher exact test was used if at least one cell contained less
than 5 observations. Chi2 test was used if all cells contain at least 5 observations each. Unpaired
T test was used to retrieve P values when comparing one nominal variable with one quota
variable, for example unpaired T test was used to retrieve P value when comparing Hb levels
between patients with primary and secondary wAIHA. All observations were unpaired,
therefore was unpaired and not paired T test used. Differences were considered of significance
at P < 0.05.
Ethics
This study has been conducted as a part of regularly quality assessment at the Division of
Hematology, Department of Medicine, Örebro University Hospital, however it was conducted
in agreement with the ethical standards of the Helsinki Declaration.
This study comprises a thorough review of patients’ journals and laboratory tests. The large
amount of patients combined with the fact that single cases are not depicted in detail, means
that is highly unlikely, if not impossible, to identify any single patient from this report.
Furthermore, any information given about patients in the study population will be presented in
a manner that obstructs recognition of single patients.
Rickard Hedberg Page 8
Aim
The purpose of this study was to create an overview of baseline characteristics and treatment
of patients with wAIHA at USÖ and to assess whether the patients are treated in accordance
with British guidelines (British Society for Haematology, 2016).
Rickard Hedberg Page 9
Patient characteristics at diagnosis
Fifty patients (19 females and 31 males), who fulfilled the inclusion criteria were included in
this study. 29 patients had primary wAIHA,
the remaining 21 patients had secondary
wAIHA.
15.8 years (range 25-88 years). Figure 1
displays the amount of patients in different
age groups at the time of diagnosis.
The mean Hb level for the entire study population at the time of diagnosis was 75.9 ± 21.9 g/l
(reference: 117-153 g/l (F), 134-170 g/l (M)).
Reticulocyte count was at diagnosis measured in 28/29 with primary wAIHA and in 20/21 with
secondary wAIHA. Reticulocyte count was 172.7 ± 131.1 109/l (ref: 30-105 109/l) in the study
population, 67 % had a reticulocyte count above reference interval.
Haptoglobin was measured in all patients except for one patient with primary wAIHA.
Haptoglobin level below reference interval was measured in 84 % of the study population. A
bilirubin level above reference interval was measured in 64 % of the study population.
DAT showed an IgG + C3 pattern in 60 % of cases and an isolated IgG pattern in 40 % of cases.
WBC above reference interval was found in 22 (44 %) of cases. Mean platelet count was found
to be 218 ± 114 109/l (ref: 165-387 (F), 145-348 (M)). Mean LD was 7.3 ± 4.0 μkat/l (ref: < 3.5
μkat/l).
Secondary wAIHA
The most common cause of secondary wAIHA in the study population was chronic lymphocytic
leukemia (CLL), 15 of 21 (71 %) cases.
Other causes included myeloproliferative disorder (n = 1), monoclonal gammopathy of
undetermined significance (n = 1), myeloma (n = 1), myelodysplastic syndrome (n = 1), splenic
lymphoma with villous lymphocytes (n = 1) and autoimmune hepatitis (n = 1).
0
5
10
15
20
25
Figure 1. Amount of patients per age group at diagnosis.
Rickard Hedberg Page 10
least once because of severe anemia. Mean Hb levels (±
1 SD) at diagnosis among patients who received
transfusion was 64.5 ± 18.4 g/l. Of those who received
transfusions, 18 (82 %) received less than 10 erythrocyte
units in total. The remaining four patients received 11, 13,
20 and 43 units of erythrocytes. Patients received a median of 4.5 units erythrocytes.
First line treatment
In all, 47/50 (94 %) patients received the recommended first line treatment of corticosteroids
(prednisolone and/or deltisone), while two patients with primary and one patient with secondary
wAIHA were observed instead of receiving first line treatment since their conditions were mild
and did not have any mentionable impact on their everyday life.
Of the 47 patients who received corticosteroids, the response was possible to determine in 46
patients. One patient had a mild condition with Hb above 100 g/l at diagnosis and Hb rarely
measured thereafter, making it not possible to determine whether the patient achieved complete
remission. In 40/46 patients (87 %) complete remission or partial remission was achieved. Of
these 40 patients, 34 (85 %) achieved complete remission. Twenty of 46 patients (43 %)
achieved complete or partial remission within day 21.
Second line treatment
Of the 47 patients who received first line treatment, 14 (30 %)
received at least one second line treatment, at a median of 21 days
after starting corticosteroid therapy.
Figure 2. Number of Units Erythrocytes Transfused.
Units Transfused
Rickard Hedberg Page 11
Rickard Hedberg Page 12
Rituximab. 11 of 50 (22 %) received at least one course of rituximab. Of the eleven patients
who received rituximab, 5 (45 %) had primary wAIHA and 6 (55 %) had secondary wAIHA.
Splenectomy. 2 of 50 (4 %) patients underwent splenectomy. One of which had a splenectomy
after treatment with corticosteroids and IViG had a poor effect on the hemolysis caused by its
primary wAIHA.
IViG. 3 of 50 (6 %) patients received treatment with IViG after 7, 10 and 11 days after start of
corticosteroid therapy. One of the patients who received IViG treatment afterwards was treated
with rituximab. The second patient only received IViG as second treatment line and achieved
neither partial nor complete remission. The third patient with IViG was reported to have a poor
response to both corticosteroids and IViG.
Other treatments. Other treatments included folic acid, calcium-D-vitamin, bisphosphonates
and thromboprophylaxis. Folic acid treatment was given to 26 of 50 patients (52 %) at any time
after diagnosis. Calcium-D-vitamin treatment was given to 20 of 50 patients (40 %) at any time
after diagnosis.
Bisphosphonate treatment was given to four patients at any time after diagnosis. One patient (4
%) of the 23 patients in the age group ≥70 years received bisphosphonates and three patients
(16 %) of the 19 patients in the age group 50-69 years received bisphosphonates. None received
specific thromboprophylaxis, while 20 patients received anticoagulants due to other conditions.
Rickard Hedberg Page 13
Comparison of primary and secondary cases
Table I compares the main characteristics of patients with primary and secondary wAIHA. At
the time of diagnosis, the biological characteristics did not differ, except for in the frequency
of increased bilirubin level (P = 0.04) and the frequency of increased WBC (P = 0.03). Bilirubin
levels were increased in 22 (76 %) of primary cases and in 10 (48 %) of secondary cases. WBC
was increased in 9 (31 %) of primary cases and 13 (62 %) of secondary cases.
Differences in DAT pattern between the two groups was found to be of significance (P = 0.047).
In the group with primary wAIHA an isolated IgG pattern was found in 15 of 29 (52 %) and an
IgG + C3 pattern in 14 of 29 (48 %), whereas in the group with secondary wAIHA 5 of 21 (24
%) had an isolated IgG pattern and the remaining 16 of 21 (76 %) was found to have an IgG +
C3 pattern. One patient with wAIHA secondary to CLL who did not receive corticosteroids
achieved a spontaneous complete remission. 13 primary and 7 secondary cases received
anticoagulants prior to diagnosis due to pre-existing conditions. TABLE I. Main Characterstics of Patients with Primary and Secondary wAIHA.
Characteristics Primary wAIHA Secondary wAIHA P value Amount of patients 29 21 Mean age at diagnosis (years) 66.1 ± 18.6 68.8 ± 11.1 0.56 Sex ratio (Females/Males) 14 / 15 5 / 16 0.08 Biological characteristics at diagnosis Mean Hb (g/L) Reference: 117-153 g/L (F), 134-170 g/L (M)
77.7 ± 17.4 72.2 ± 22 0.34
High WBC n (%) Reference: 3.5-8.8 x109/L
9 (31 %) 13 (62 %) 0.03
Mean Platelet count (109/L) Reference: 165-387 x109/L (F), 145-348 x109/L (M)
228.8 ± 127.4 202.3 ± 92.9 0.42
Mean Reticulocyte count (109/L) Reference: 30-105 x109/L
194 ± 139.5 143 ± 109.9 0.18
High Reticulocytes n (%) 21 (75 %) 11 (55 %) 0.15 Low Haptoglobin n (%) 26 (93 %) 15 (71 %) 0.06 Elevated Bilirubin level n (%) 22 (76 %) 10 (48 %) 0.04 LD Reference: < 3.5 μkat/L
7.6 ± 4.3 7.0 ± 3.8 0.59
DAT pattern IgG n (%) 15 (52 %) 5 (24 %) 0.047 IgG + C3 n (%) 14 (48 %) 16 (76 %) 0.047 C3 n (%) 0 (0 %) 0 (0 %) Treatment Need for transfusion n (%) 12 (41 %) 10 (48 %) 0.79 Patients with corticosteroids n (%) 27 (93 %) 20 (95 %) 1 Corticosteroid response…
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