Ijms 25 04296 v3
Ijms 25 04296 v3
Ijms 25 04296 v3
Molecular Sciences
Review
Autoimmune Hemolytic Anemias: Classifications,
Pathophysiology, Diagnoses and Management
Melika Loriamini 1,2 , Christine Cserti-Gazdewich 1,3,4 and Donald R. Branch 1,2,5, *
Abstract: Autoimmune hemolytic anemias (AIHAs) are conditions involving the production of
antibodies against one’s own red blood cells (RBCs). These can be primary with unknown cause or
secondary (by association with diseases or infections). There are several different categories of AIHAs
recognized according to their features in the direct antiglobulin test (DAT). (1) Warm-antibody AIHA
(wAIHA) exhibits a pan-reactive IgG autoantibody recognizing a portion of band 3 (wherein the
DAT may be positive with IgG, C3d or both). Treatment involves glucocorticoids and steroid-sparing
agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. (2) Cold-antibody
AIHA due to IgMs range from cold agglutinin syndrome (CAS) to cold agglutin disease (CAD). These
are typically specific to the Ii blood group system, with the former (CAS) being polyclonal and the
latter (CAD) being a more severe and monoclonal entity. The DAT in either case is positive only
with C3d. Foundationally, the patient is kept warm, though treatment for significant complement-
related outcomes may, therefore, capitalize on monoclonal options against C1q or C5. (3) Mixed
AIHA, also called combined cold and warm AIHA, has a DAT positive for both IgG and C3d, with
Citation: Loriamini, M.; Cserti-
treatment approaches inclusive of those appropriate for wAIHA and cold AIHA. (4) Paroxysmal cold
Gazdewich, C.; Branch, D.R.
hemoglobinuria (PCH), also termed Donath–Landsteiner test-positive AIHA, has a DAT positive only
Autoimmune Hemolytic Anemias:
for C3d, driven upstream by a biphasic cold-reactive IgG antibody recruiting complement. Although
Classifications, Pathophysiology,
Diagnoses and Management. Int. J.
usually self-remitting, management may consider monoclonal antibodies to C1q or C5. (5) Direct
Mol. Sci. 2024, 25, 4296. https:// antiglobulin test-negative AIHA (DAT-neg AIHA), due to IgG antibody below detection thresholds in
doi.org/10.3390/ijms25084296 the DAT, or by non-detected IgM or IgA antibodies, is managed as wAIHA. (6) Drug-induced immune
hemolytic anemia (DIIHA) appears as wAIHA with DAT IgG and/or C3d. Some cases may resolve
Academic Editor: Balik Dzhambazov
after ceasing the instigating drug. (7) Passenger lymphocyte syndrome, found after transplantation, is
Received: 11 March 2024 caused by B-cells transferred from an antigen-negative donor whose antibodies react with a recipient
Revised: 1 April 2024 who produces antigen-positive RBCs. This comprehensive review will discuss in detail each of these
Accepted: 3 April 2024 AIHAs and provide information on diagnosis, pathophysiology and treatment modalities.
Published: 12 April 2024
only a few days [1–4]. The internal components of red blood cells are released into the
circulation and surrounding tissues, producing specific symptoms related to the condi-
tion [3]. Autoantibodies usually target antigens found on virtually all RBCs and a direct
antiglobulin test (DAT) is useful in the diagnosis [3]. Because patients with AIHA often
require transfusion to address their anemia, finding compatible blood is challenging [3,9,10].
Fortunately, transfused blood survives, as does the patient’s own, so the transfusion of
antigen-selected units despite incompatibility should not be withheld [3,10]; in so doing, it
is imperative to rule out underlying alloantibodies that could differentially interact with
the transfused donor blood [8,9].
AIHA should be suspected if the patient shows signs and symptoms of anemia and
other causes of the anemia, such as bleeding, underproduction, paroxysmal nocturnal
hemoglobinuria (PNH), and other potential causes of anemia have been ruled out [3],
see Section 1.1 above. The most important serological test for the diagnosis of AIHAs
is the DAT using polyspecific and monospecific anti-human globulins (AHG) [3,12,22].
The initial testing should be with a DAT using a polyspecific AHG that contains anti-
IgG and anti-C3d. If positive, then the DAT should be performed with monospecific
AHG, one containing anti-IgG and one containing anti-C3d. Table 2 shows the expected
results for the DAT depending on the particular type of AIHA. The antibody may only
react by an indirect antiglobulin test (IAT) in wAIHA and mixed AIHA. In cold-antibody
AIHA, the antibody is an IgM cold agglutinin that reacts better in colder temperatures
(i.e., ≤room temperature) and involves (recruits and activates) complement so that the
DAT will be positive only with polyspecific and monospecific anti-C3d AHG. In mixed
AIHA, the IgG antibody reacts in the IAT while the IgM antibody is an agglutinating
antibody having low titer but high thermal activity (≤37 ◦ C). PCH will present with a
positive DAT due to anti-C3d only; however, the serum autoantibody is an IgG bi-phasic
hemolysin that is detected using the Donath–Landsteiner (D-L) test and recognizes the
P-blood group system. Thus, it is non-reactive with p RBCs. Using standard “blood bank
techniques for DAT and elution”, the DAT, eluate and serum antibody are negative in
DAT-neg AIHA; however, the DAT can be shown to be positive with IgG using specialized
tests such as Western immunoblotting [24]. Drug-induced AIHA serologically presents as
indistinguishable from wAIHA. Diagnosis in drug-dependent forms is established when
stopping the suspected drug resolves the destruction, though some drugs may trigger true
wAIHA via iatrogenic immune dysregulation [3,26]. Passenger lymphocyte syndrome is
diagnosed when following a solid organ or bone marrow transplant, the patient develops
an antibody to the recipient’s RBCs. While presenting serologically as a wAIHA, with or
without specificity, it is owing to the donor’s B-cells producing an antibody to the recipient’s
residual RBCs [17,25].
Int. J. Mol. Sci. 2024, 25, 4296 4 of 18
** Diagnosis made using Donath-Landsteiner (D-L) Test, usually anti-GLOB, fails to react with p RBCs; *** IgG
can be found in the DAT using special tests but not with standard serological tests or in eluates using standard
methods; ˆ Can be positive with C3d; & Usually has specificity within ABO (anti-A or anti-B) or Rh (anti-D) blood
group system.
1.3. Incidence
Based on current calculations, the yearly occurrence of AIHA is 1–2 cases per
100,000 persons [18]. Out of all the instances, wAIHA is the most common type, account-
ing for two-thirds of all cases [3,18,19]. CAS/CAD is the second most common AIHA,
accounting for 15–20% of cases [3,20]. Mixed AIHA is the third most common AIHA, as
a co-presentation of both wAIHA and cold-antibody AIHA [2,3]. PCH is a rare illness
disproportionately seen in children and associated with infections [3,21]. DAT-negative
AIHA is rare [3,22] and difficult to diagnose [24]. Passenger lymphocyte syndrome (PLS)
occurs after transplantation and is related to the immune cells from the donor, transferred
via the graft, subsequently producing host-specific anti-RBC antibodies, thereby mimicking
AIHA [17,25]. In the future, the incidence of AIHA may increase due to the use of stem cell
transplantation and checkpoint inhibitors in the treatment of cancers [27,28].
RBCs. For example, warm autoantibodies that reacted with all normal RBCs but not with
-D- and Rhnull RBCs were termed anti-nl (non-deleted or normal), while autoantibodies
that would react with all normal RBCs and with -D- but not Rhnull were termed anti-pdl
(partially deleted). Finally, autoantibodies that would react with normal, as well as with
both -D- and Rhnull , were termed anti-dl (fully deleted) autoantibodies [3]. Subsequently,
other specificities were reported to exist; for example, anti-Jka , anti-Gerbich, anti-LW and
anti-Kell [3,42,43]. Other scientists found autoantibodies reacting with components of band
3 on the RBCs [3,42]. As investigators dealt with the various specificities reported and
were using Rhnull and -D- RBCs to determine the anti-nl, anti-pdl or anti-dl specificity of
these autoantibodies, two groups, independently, found that in the majority of patients
with wAHIA, autoantibodies reacted preferentially with older, reticulocyte-depleted RBCs
and reacted much less or not at all with younger, reticulocyte-enriched RBCs [44,45]. Both
groups found that the frequency of reactivity was 80% of patients with wAIHA for the
former and 20% for the latter. Thus, warm autoantibodies in 80% of the cases showed a
tropism to “old RBCs” compared to “young RBCs”. One group termed this specificity as
Type I wAIHA versus Type II wAIHA (20% of patients) with wAIHA showing no RBC age
preference [45]. These investigators suggested that Type I wAIHA could be an exacerbation
of the normal clearance mechanism in RBC senescence, whereby natural autoantibodies
deplete old RBCs by targeting band 3 [45–48].
More recently, teams have shown that most warm autoantibodies do, in fact, target
band 3 [42,49,50]. In a recent publication, the authors confirm Type I and Type II wAIHA
and suggest that Type I wAIHA autoantibodies target band 3 and that the hemolytic
anemia may conversely involve patient RBCs that are also aging faster than normal [48].
Type I patients’ RBCs, by aging faster, expose the immune system to more senescent RBC
antigen, which in turn stimulates more autoantibody to senescent band 3, producing a
functional autoimmune disease [42]. In contrast, patients with Type II wAIHA showed a
lack of RBC aging, suggesting rapid and equal-opportunity opsonisation and the removal of
RBCs [49], consistent with a previous report of Type II wAIHA being more severe than Type
I wAIHA [44]. Additional investigations show that the natural autoantibody that binds
to aged RBCs, indeed, recognizes band 3 [49,50]. Taken together, these findings generate
the hypothesis that most wAIHA patients, at 80%, produce more of the senescent RBC
autoantibody that reacts with patients’ accelerated aging RBCs, for Type I wAIHA [42,49].
Another implication from this work is that the specificity of the autoantibody in Type
II wAIHA may be to other RBC antigens (non-band 3) [3,45]. These hypotheses require
further verification.
2.2. Biomarkers
Identifying biomarkers specific to particular disease states is an ongoing quest by
biomedical researchers. Although in AIHAs, the DAT is a true biomarker with classifica-
tion power (Table 3), signature cytokines may also qualify as biomarkers, given specific
associations in wAIHA [51–54]. In the most comprehensive report [51], 54 patients having
DAT+ wAIHA were compared with 36 healthy controls for 38 cytokines, chemokines or
growth factors using a multiplex approach and Luminex technology. This found that
TNFα and interleukin 10 (IL-10) are the most increased in wAIHA, with IL-8/CXCL8 and
IP10/CXCL10 being elevated and, hence, potentially eligible as biomarkers too. Taken
together, wAIHA patients have four possible cytokine/chemokine biomarkers, with TNFα,
IL-10, IL-8/CXCL8 and IP10/CXCL10, and perhaps IL-6 [53]. Future studies may validate
this repertoire.
Int. J. Mol. Sci. 2024, 25, 4296 7 of 18
Category Pathophysiology Primary Target Antigen DAT as Biomarker First-Line Treatments &
Extravascular hemolysis Glucocorticoids,
wAIHA Band 3 IgG ± C3d
* steroid-sparing agents #
Intravascular hemolysis
CAS I/i antigens C3d only Keep warm
**
Intravascular hemolysis
CAD I/i antigens C3d only Anti-C1q/-C5
**
Intra- and wAIHA, CAS,
Mixed AIHA Band3; I/i antigens IgG + C3d
extravascular hemolysis CAD options
PCH Intravascular hemolysis GLOB (formally P antigen) C3d Anti-C1q/-C5, Rituximab
DAT-neg AIHA Extravascular hemolysis Unk negative wAIHA options
Intra- and
DIAIHA Unk ˆ IgG and/or C3d Discontinue drug
extravascular hemolysis
antigen-negative
transfusion support;
PLS Extravascular hemolysis ABO/Rh IgG
may adjust
anti-rejection regimen
DAT, direct antiglobulin test; wAIHA, warm-antibody autoimmune hemolytic anemia; CAS, cold agglutinin
syndrome; CAD, cold agglutinin disease; PCH, paroxysmal hemoglobinuria; DIAIHA, drug-induced autoim-
mune hemolytic anemia; PLS, passenger lymphocyte syndrome. & Transfusion if necessary; do not withhold
transfusion if physiologically required; incompatible transfused blood (emulating the recipient antigen profile) is
expected to have survival similar to autologous blood; caveats relate to underlying alloantibodies, which may
be detected in adsorption studies or anticipated by recipient antigen profiling (genotyping, or where feasible,
phenotyping). Depths of matching (mirroring what the patient is antigen-negative for, at a minimum in the
Weiner-Kell system, and ideally beyond this in the Kidd, Duffy, and S systems) are key to avoiding missed
antibodies, preventing the formation of new specificities, and helping to reduce the workload of adsorption
studies assessing for residual/emerging alloantibodies permitted by historic match gaps. * Mediated by monocyte-
macrophage phagocytosis of IgG and/or complement opsonized RBCs. Possibly intravascular, mediated by
antibody-dependent cellular cytotoxicity (ADCC). # First choice treatment; other treatments are available such as
rituximab, daratumumab and kinase inhibitors (see Text). ** Mediated by complement activation. ˆ Target antigen
requires the presence of the drug (in vivo and/orin vitro).
2.3. Treatment
wAIHA is usually initially treated with glucocorticoids [3,55–59]. While glucocor-
ticoids often achieve a partial or complete remission, difficult or dependent cases may
command other treatments such as off-label rituximab (anti-CD20), IVIG, or daratumumab
(anti-CD38). Other investigational agents such as FcγRn inhibitors (nipocalimab), Syk ki-
nase inhibitors (fostamatinib), BTK kinase inhibitors (rilzabrutinib), or PI3 kinase inhibitors
are being explored [57–64]. If complement-mediated hemolysis is suspected, treatment
may include inhibitors of the complement pathway such as sutimlimab (anti-C1s) or
eculizumab (anti-C5) [58,60,63,65]. There continues to be active research on new therapies
for wAIHA [58,63–68]. Although splenectomy was used for years with immense success,
it is rarely used today [3,60]. In a recent cohort study of 1824 patients, splenectomy was
found to be an effective treatment, though with surgical complications in 12% [69].
3.3. Treatment
Treatment for CAS usually involves keeping the patient warm until the condition
resolves with convalescence from the underlying disease. Maneuvers include blanketing
or maintaining higher ambient room temperatures at 37 ◦ C–40 ◦ C, and if transfusion is
required, using a blood warmer. In severe cases of CAS, one may use sutimlimab (anti-
C1s) [79–86].
CAD is a more difficult-to-treat AIHA, as the antibody is usually associated with a
chronic disease and the monoclonal antibody produced can cause more severe anemia than
in CAS [79–86]. Therefore, treatment can consist of rituximab or anti-complement thera-
pies such as sutimlimab to block the classical complement activation pathway [58,65,79–82]
or eculizumab to block the membrane attack complex of complement activation
pathway [58,78,83,84]. To limit the production of the causal antibody and to diminish
the cellular biomass of the driving condition, rituximab with or without strong immuno-
suppressive drugs such as fludarabine or bendamustine may be prescribed [58,78,83,84].
Recently, the use of daratumumab (anti-CD38) has been shown to be effective in the
treatment of relapsing CAD [64,83,84].
Treatment
Treatment usually involves glucocorticoids with patients having a good and rapid
response [39]. However, again, rituximab and/or complement inhibitors may be consid-
ered [60,91]; see treatments under wAIHA and CAD above.
Int. J. Mol. Sci. 2024, 25, 4296 9 of 18
5.2. Treatment
PCH in children is usually self-remitting. In severe cases requiring transfusion, ap-
proaches that have been successfully described include plasma exchange, rituximab, and
complement inhibitors such as eculizumab [3,97,101–104].
6. DAT-Neg AIHA
Approximately 1% to 10% of people diagnosed with AIHA have a negative
DAT [3,103,104]. The DAT is a diagnostic technique that has a sensitivity range from
92% to 97% for detecting AIHA. The diagnosis of DAT-neg AIHA mostly relies on the
method of excluding other possible causes [3,12,105–107]. Several key variables contribute
to the development of DAT-neg AIHA. These factors include the following: (a) the exis-
tence of red blood cell-bound IgG at levels that are too low to be detected using standard
methods [3,24,105]; (b) the relatively weak binding strength of IgG [3]; (c) the lack of a
positive eluate using standard methods; and (c) the presence of RBC-bound IgA where
AHG contains only antibodies to IgG [3,73] or, in rare instances, IgA or IgM [3,22,29,32,108].
In the early 1970s, Gilliland and colleagues [3,105] were the first to emphasize that
the amount of antibodies found on RBCs in patients with AIHA may be insufficient to
detect by standard DAT reagents. They proposed that the distribution of IgG antibodies on
circulating RBCs was non-uniform. RBCs accumulate IgG as they age, leading to a larger
ratio of IgG to RBCs in older RBCs compared to younger ones [44,45,49,50,105].
In some instances of DAT-neg AIHA, less often encountered immunoglobulins, namely
IgA and IgM, may be identified on the outside of RBCs using a DAT with special antibod-
Int. J. Mol. Sci. 2024, 25, 4296 10 of 18
ies [3,22,29,32,33,108]. IgA AIHA has a clinical picture that closely matches that of IgG
wAIHA [106]. While the standard DAT may yield negative results, the use of special DAT
reagents that can detect IgM and IgA may be useful [3]. Western immunoblotting may
detect IgG on RBCs below the detection level of a DAT and could be useful to diagnose
DAT-neg AIHA [24]. This technique could also be adjusted to monitor IgA and IgM levels
on RBCs in DAT-neg AIHA. Most instances of IgM AIHA are caused by the presence of a
pathological cold autoantibody that has a broad temperature range and may respond at
temperatures ranging from 30 ◦ C to 37 ◦ C (see Sections 3 and 4, above). Diagnosing warm
IgM AIHA might be difficult since there are no significant serological findings. Antibody
detection tests may exhibit little reactivity. Both pathogenic IgM cold autoantibodies and
warm IgM autoantibodies exhibit the presence of complement coating on the patient’s
RBCs. As a result of this feature, some people with warm IgM AIHA may be misdiagnosed
with CAD or PCH [3,32].
Treatment
Treatment for severe cases of DAT-neg AIHA would be similar as to those used for the
treatment of wAIHA (see Section 2 above).
7.3. Treatment
The treatment for these drug-induced conditions often simply involves stopping the
drug therapy, if possible, or switching to a different, chemically unrelated, drug. When this
is done, the hemolysis may abruptly cease [16,26,38]. If the hemolysis is severe, one can
treat the patient with similar therapies as used for the treatment of wAIHA.
obtained from the donor, and these can be transferred into the recipient [114–118]. It is
feasible for donor lymphocytes that have been transferred to produce antibodies that are
specific to RBC antigens in the recipient’s body but not present on the donor’s own red
cells [17,25,112–118]. Indeed, sometimes these passenger lymphocytes in either BMT or
solid organ transplants are obtained from donors who have been sensitized to produce
alloantibodies to antigens for which they lack. Thus, passenger lymphocytes from a blood
group O donor transferred into a recipient of blood group A can produce anti-A that
can react with and hemolyze the residual RBCs in the recipient due to those being blood
group A. Likewise, passenger lymphocytes from a donor who is Rh-negative but who
has been sensitized to produce anti-D can induce a hemolytic anemia in an Rh-positive
recipient, which may manifest as a delayed-type hemolytic reaction. In both instances, the
hemolytic anemia can appear as an AIHA, though with an apparent specificity. Indeed, if
this syndrome occurs, its presentation as immune hemolysis after a transplantation may
be misinterpreted as autoimmune hemolytic anemia. The hemolysis can be severe with
outcomes such as renal failure [114,116,117].
8.2. Treatment
It is critical to recognize that the stem cell or solid organ transplant patient who is
hemolyzing may be manifesting PLS. Treatment may require the transfusion of antibody-
evading (donor blood type) RBCs, i.e., blood group O cells if hemolysis is due to ABO
antibodies (in a group O donor to a non-O recipient). If anti-D or other alloantibodies
are identified as the cause of the hemolysis, then antigen-negative donor blood should be
used for transfusion [17,113,115]. If hemolysis is severe, one can treat with changes to the
immunosuppressive regimen [113,118] or combine the regimen with IVIG or plasmaphere-
sis [117].
9. Current Opinion
We believe that hyperhemolysis syndrome (context: sickle cell disease (SCD) or other
diagnoses) deserves its own category within AIHA. Although it is a distinctly transfusion-
triggered event, with the absence or presence of an involved alloantibody cognate to a
triggering unit, once triggered, it appears to be an autoimmune-like phenomenon with
extreme bystander hemolysis [120] (kinetically akin to post-transfusion purpura (PTP)).
The complement cascade appears important (as judged by the response of some cases to
eculizumab), with hyperinflammation occurring (as judged by the greater responsiveness
to IVIG with high-dose steroids, +/− the utility of anti-cytokine storm interventions such
as tocilizumab). In virtually every regard, this is a pathology that is not addressed by
any of the conventional AIHA categories. However, because it manifests in part with an
autologous response, there is an argument for its inclusion in the taxonomy of AIHA, just
as there are arguments for the inclusion of passenger lymphocyte syndrome.
Author Contributions: Conceptualization, M.L., C.C.-G. and D.R.B.; Writing—original draft prepara-
tion, M.L.; Writing—review and editing, C.C.-G. and D.R.B. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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