TYPE Review

PUBLISHED 18 September 2023

DOI 10.3389/fimmu.2023.1228142

Severe autoimmune hemolytic

OPEN ACCESS anemia; epidemiology, clinical
EDITED BY
Jeffrey J. Pu,
Harvard Medical School, United States
management, outcomes
REVIEWED BY
Angel Robles-Marhuenda,
and knowledge gaps
La Paz Hospital, Spain
Nancy Van Buren,
New York Blood Center, United States Femke V. M. Mulder 1,2*, Dorothea Evers 3, Masja de Haas 1,2,4,
*CORRESPONDENCE Marjan J. Cruijsen 5, Sophie J. Bernelot Moens 6,
Femke V. M. Mulder
f.mulder@sanquin.nl
Wilma Barcellini 7, Bruno Fattizzo 7,8 and Josephine M. I. Vos 4,6
RECEIVED 24 May 2023
1
Sanquin Research and Landsteiner Laboratory, Translational Immunohematology, Amsterdam UMC,
ACCEPTED 28 August 2023
Amsterdam, Netherlands, 2 Department of Hematology, Leiden University Medical Center,
Leiden, Netherlands, 3 Department of Hematology, Radboud University Medical Center,
PUBLISHED 18 September 2023
Nijmegen, Netherlands, 4 Department of Immunohematology Diagnostics, Sanquin Diagnostic
CITATION Services, Amsterdam, Netherlands, 5 Department of Hematology, Catharina Hospital,
Mulder FVM, Evers D, de Haas M, Eindhoven, Netherlands, 6 Department of Hematology and Amsterdam Institute for Infection and
Cruijsen MJ, Bernelot Moens SJ, Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 7 Department of
Barcellini W, Fattizzo B and Vos JMI (2023) Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, 8 Department
Severe autoimmune hemolytic anemia; of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
epidemiology, clinical management,
outcomes and knowledge gaps.
Front. Immunol. 14:1228142.
doi: 10.3389/fimmu.2023.1228142
Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder,
COPYRIGHT
© 2023 Mulder, Evers, de Haas, Cruijsen, mediated by auto-antibodies, and has a variable clinical course ranging from
Bernelot Moens, Barcellini, Fattizzo and Vos. fully compensated low grade hemolysis to severe life-threatening cases. The
This is an open-access article distributed
under the terms of the Creative Commons
rarity, heterogeneity and incomplete understanding of severe AIHA complicate
Attribution License (CC BY). The use, the recognition and management of severe cases. In this review, we describe
distribution or reproduction in other how severe AIHA can be defined and what is currently known of the severity and
forums is permitted, provided the original
author(s) and the copyright owner(s) are outcome of AIHA. There are no validated predictors for severe clinical course,
credited and that the original publication in but certain risk factors for poor outcomes (hospitalisation, transfusion need and
this journal is cited, in accordance with
mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA
accepted academic practice. No use,
distribution or reproduction is permitted (warm AIHA with complement positive DAT, mixed, atypical) are associated with
which does not comply with these terms. lower hemoglobin levels, higher transfusion need and mortality. Currently, there
is no evidence-based therapeutic approach for severe AIHA. We provide a
general approach for the management of severe AIHA patients, incorporating
monitoring, supportive measures and therapeutic options based on expert
opinion. In cases where steroids fail, there is a lack of rapidly effective
therapeutic options. In this era, numerous novel therapies are emerging for
AIHA, including novel complement inhibitors, such as sutimlimab. Their potential
in severe AIHA is discussed. Future research efforts are needed to gain a clearer
picture of severe AIHA and develop prediction models for severe disease course.
It is crucial to incorporate not only clinical characteristics but also biomarkers
that are associated with pathophysiological differences and severity, to enhance
the accuracy of prediction models and facilitate the selection of the optimal
therapeutic approach. Future clinical trials should prioritize the inclusion of
severe AIHA patients, particularly in the quest for rapidly acting novel agents.

KEYWORDS

autoimmune hemolytic anemia, cold agglutinin disease, severe, mortality, management

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Introduction Defining severe AIHA

Autoimmune hemolytic anemia (AIHA) is a rare condition, Severe or fulminant AIHA is poorly defined, as described in a
with an incidence of 1-3 per 100,000 per year (1–3). It is recent review on terminology in AIHA (11). Only 2 of 61 identified
characterized by an increased destruction of red blood cells articles define severe AIHA, both with different hemoglobin (Hb)
(RBC) due to autoantibodies that takes place extravascularly cut-offs, one extending the definition with need of daily transfusion
(spleen and liver) or in rare occasions intravascularly. Generally, (12, 13). Importantly however, hemoglobin at onset, while an easily
the diagnosis is based on markers of hemolysis and a positive direct available parameter, can be affected by many factors, such as
antiglobulin test (DAT), that detects antibodies and/or complement accessibility to medical care, comorbidities and age. For example,
on the red blood cells of the patient. Various entities are recognized, younger patients generally present with lower hemoglobin levels
i.e. warm AIHA (wAIHA), cold AIHA (cAIHA) and mixed or (12, 14), potentially representing a more severe subgroup, but this
atypical AIHA (4). These subtypes are distinguished by might also be related to a higher tolerance of severe anemia leading
characteristics and effects of the red blood cell reactive to delayed presentation.
autoantibodies, particularly their immunoglobulin class (IgG, Certain studies categorize by severity of hemolysis, as
IgM, IgA), thermal amplitude and the extent of antibody- determined by laboratory parameters of hemolytic activity,
mediated complement activation. In wAIHA, autoantibodies are instead of outcome measures (15–17). Das et al. and Ray et al.
mostly of IgG class and red blood cell destruction typically occurs labelled cases as having ‘severe hemolysis’ if all four of the following
via binding by IgG-Fc receptors on macrophages in the spleen, conditions were met: Hemoglobin <9 g/dL, indirect bilirubin >2
although some IgG antibodies may also activate complement. Cold mg/dl, reticulocyte count >2% and LDH >500IU/L. Cases with less
agglutinins (CA) are mostly IgM antibodies that bind to the RBC than four aberrant values are labelled as ‘moderate hemolysis’. Of
(typically I antigen) at low temperatures, inducing agglutination note, in this algorithm, a case with a low reticulocyte count might be
and complement activation and subsequent red blood cell labelled as having ‘moderate hemolysis’, whilst this may in fact
destruction. The latter occurs mainly in the liver via C3b represent patients with inadequate bone marrow compensation,
deposition on RBCs. However, in case of terminal complement possibly a subgroup with increased risk for severe outcomes.
activation, this may culminate into intravascular hemolysis. Recently, the first international consensus group defined severe
AIHA is classified as either primary or secondary to an underlying AIHA as when the unsupported Hb level falls below 8g/dL and
disease, including lymphoproliferative disorders, immunodeficiencies, transfusion is required with an interval ≤ 7 days (4). While the
infectious diseases and other auto-immune diseases (5). Primary decision for transfusion is multifactorial, at least this definition
cAIHA is referred to as cold agglutinin disease (CAD). The CAs are contains a clinical outcome measure that may capture the complex
produced by an indolent B-cell lymphoproliferation in the bone interplay of various factors related to disease severity (which
marrow. In the most recent revision of the WHO classification, the encompasses not only severity of hemolysis but also transfusion
presence of a B-cell clone and CAs is defined as a separate entity called efficacy, bone marrow compensatory capacity, comorbidities,
CAD-Lymphoproliferative disorder (CAD-LPD) (6). If cold tolerance of hemoglobin level, organ failure et cetera).
agglutinins arise in the context of another underlying disease such as Refractory AIHA is a separate specific subgroup, sometimes
overt malignancy or infection, this is referred to as cold agglutinin referred to as severe cases as well. In this review we focus on severe
syndrome (CAS) (4). rather than refractory AIHA, although these populations may
The clinical course of AIHA is highly diverse and AIHA well overlap.
patients vary not only in underlying diseases, but also in factors
such as the antibody isotype, site of red cell destruction,
involvement of the complement system, and the bone marrow’s AIHA severity and mortality
compensatory capacity. Given this heterogeneity, predicting the
course of the disease in individual cases is challenging. Many AIHA AIHA severity definitions as per the first consensus meeting or
patients solely require outpatient care. However, several case by any other definition have not been validated in clinical studies.
reports and series have illustrated that AIHA can culminate into Consequently, incidence, characteristics and outcomes of this
a fulminant and even fatal clinical course (7–10). These patients subgroup have not been established. As a surrogate, data on
may deteriorate rapidly due to massive hemolysis, leading to organ hemoglobin levels, transfusion burden, hospitalisation, ICU
failure, and require repeated blood transfusions and treatment in an admissions and mortality in the general AIHA population will
intensive care unit (ICU). be discussed.
In this article, we review the available literature on severe and
fatal AIHA, with a focus on definitions, epidemiology including
mortality and causes of death, and risk factors associated with Hemoglobin, transfusions and
unfavorable outcomes. We also summarize available data on hospital admissions
treatment and formulate recommendations for the clinical
management of fulminant hemolytic episodes. Finally, we point The Italian GIMEMA group published data on the largest
out knowledge gaps and areas for future research. cohort of AIHA patients so far (n=378, follow-up approximately

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4 years), consisting of only primary cases (12, 18). In this cohort failure on admission. In total, 13/44 patients (30%) died in the
median hemoglobin at onset was around 7-7.5g/dL, with 63% below ICU, with causes of death being organ ischemia, sepsis and
8 g/dL and 27% below 6 g/dL. In a subgroup with more detailed haemorrhage Organ failure upon ICU admission was associated
data, health care resource utilisation was analysed (n=190). Of these with mortality, however, also 4 (21%) of the patients without any
patients, 54% required blood transfusions at some point, ranging organ failure upon admission died. In a larger multicenter study,
from 1 up to 41 units per year (median 2). Hospital admission was performed over the period 2013 to 2020, only ICU admissions
required at least once (up to 8 times) in 64% of the patients during primarily for AIHA were included (n=62, 64% secondary AIHA)
the median follow-up of 4.3 years. Whether transfusions and and compared to a control group of AIHA patients not requiring
hospitalizations were due to AIHA, was not specified. The wide ICU admission (23). In the AIHA ICU group, 90% received
range of transfusions and hospitalisations illustrates the clinical transfusions with a median of 1.5 (range 1.0-2.5) units per day.
heterogeneity of AIHA. Transfusion rates and inpatient Multivariate analysis identified hemoglobin and indirect bilirubin at
hospitalisation rates were significantly higher in wAIHA with IgG onset as risk factors for ICU admission. During ICU stay, 13% of the
plus complement positive DAT, atypical (including IgA mediated AIHA patients died after a median of 3.5 days. Causes of death were
and DAT negative forms) and mixed cases. The authors classified cardiac arrest due to refractory AIHA in 5 patients and massive
10-15% of cases as ‘severe/ultra-refractory’ AIHA, based on the fact pulmonary embolism in 3. It is important to note that 92% of this
that their hospital stays exceeded 30 days, transfusion exceeded 20 cohort displayed inadequate reticulocytosis (Bone Marrow
units per year and certain drugs were administered (bortezomib, Reticulocytes Index (BMRI) < 121), likely contributing to more
rituximab, eculizumab). This group mainly consisted of CAD, severe anemia. However, in multivariate logistic regression analysis,
wAIHA with IgG plus complement positive DAT, mixed and a BMRI <121 was no significant risk factor for ICU admission
atypical cases. compared to the non-ICU AIHA group. Of all ICU survivors, 9.3%
In CAD, hemoglobin levels are generally higher than in other was readmitted to the ICU for AIHA relapse within 1 month. Nine
AIHA subtypes. The largest retrospective multinational cohort of patients died within one year, of which 6 had ongoing hemolysis at
CAD patients (n=232) (19), showed that the median hemoglobin at time of death. Causes of death were progression underlying disease
onset was 9.3 g/dL with 27% of the cohort below 8 g/dL. Up to 47% (n=3), infection (n=3), pulmonary embolism (n=1), hemorrhagic
of patients received at least one RBC transfusion during the median shock of iatrogenic wound (n=1) and multiorgan failure due to
6 years of follow-up, which is comparable with 51% in the CAD massive hemolysis (n=1).
subgroup in the GIMEMA study (median follow-up 4 years) (18).
In both of these cohort studies (18, 19), AIHA-specific
transfusions, hospitalisations and complications were not Mortality and causes of death
recorded, nor compared to a control group. Two registry-based
studies (US and Denmark) analyzed health care utilization by CAD The mortality in the GIMEMA cohort (primary AIHA) was
patients in comparison to a control group (matched for age, sex and 20% during > 4 years of follow-up, and 11 (3.6% of total cohort)
comorbidity index scores) (20, 21). In both studies, transfusion need deaths were ascribed to AIHA, with causes of death being infection
within 12 months after disease onset was significantly increased in 5, myocardial infarction in 1, pulmonary embolism in 1 and
(23.7 vs. 2.1% and 43% vs 1.3% in matched controls). The multiorgan failure in 4 (12). In the extended cohort (n=378),
percentage of patients requiring inpatient hospitalisation at least significant risk factors for fatal outcome were lower hemoglobin
doubled (36% vs. 15% and 53% vs. 23% in matched controls), and at onset (<8 g/dl), presence of Evans syndrome, infections and acute
the odds for hospitalisation was 3.9 times higher (20, 21). Similar renal failure. No association with thrombotic events and type of
studies for wAIHA do not exist, but one French population-based AIHA was found (18). The GIMEMA cohort solely consists of
study found increased hospitalisation rates for thrombosis (HR 1.9) primary cases, allowing for analysis of the effect of AIHA itself,
and infections (HR 4.1) in AIHA (no differentiation between rather than the underlying disease. Secondary AIHA is a very
subtypes) compared to matched comparisons from the general heterogenous group with varying proportions of underlying
population (2). diseases observed among different cohorts and geographic
locations (5). Some underlying diseases such as malignancies may
have higher mortality rates, regardless of AIHA course, whereas
ICU admissions AIHA cases with a temporary trigger such as mycoplasma infection,
might never relapse.
There are no studies reporting on the incidence or frequency of In several (predominantly) adult cohorts (8 studies, n=525)
ICU admissions in patients with AIHA. Recently, two French with both primary and secondary wAIHA, mortality rates range
cohorts of AIHA patients admitted to the ICU were published from 3-20% (24–31). In almost half of the deaths, the cause was
(22, 23). In a single center study, reviewing data over the period unknown or not reported. If mentioned, causes of death were
2002-2015, 44 patients were admitted to the ICU department with mainly infections (n=21), malignancies and thrombotic events. A
AIHA (89% secondary AIHA). In 21 of those, ICU admission was clear link with a hemolytic episode is stated in some cases (26, 29),
primarily because of AIHA, of which all but 2 were admitted for but is generally unknown or not reported. The small cohort sizes,
extensive monitoring and transfusion but did not show organ heterogeneity of disease and varying median follow-up times (0-4

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Mulder et al. 10.3389/fimmu.2023.1228142

years), as well as the lack of a control group limit the interpretation. primary immunodeficiency. Increased mortality due to bleeding is
The largest multinational (‘primary’) CAD cohort (n=232) difficult to interpret, as no details on type of bleeding are available,
analysed survival rates and estimated the five-year mortality at but could be related to concomitant ITP (Evans syndrome) or
17%. In this cohort, 11% (3.5% of total cohort) of deaths were anticoagulation therapies for (prevention of) thrombotic
ascribed to CAD or its complications (19). Specific causes of death complications. For all causes of death, the time-relation between
and their correlation with hemolytic episodes were not discussed. deaths (i.e., cardiovascular) and hemolytic episodes remains unclear
Two recent population-based studies on AIHA mortality based on the currently available data. Therefore, drawing
compared outcomes to an age and sex matched control group conclusions on causal mechanisms and high-risk conditions for
from the general population, and report hazard ratios adjusted for AIHA patients remains difficult.
comorbidities (aHR). In a French population-based cohort, the
one-year mortality was 17.9% (aHR 2.9) for primary AIHA, 28.4%
(aHR 3.5) for secondary AIHA with hematological malignancies Risk factors for severe clinical course
and 14.3% (aHR 4.6) for other secondary AIHA (2). The diagnosis and mortality
of AIHA in this study was based on ICD codes, therefore different
subtypes of AIHA (cold, warm, mixed) were not distinguished. A Overall, there are no validated prognostic tools to predict the
Danish population-based cohort showed similar one-year clinical course of AIHA. However, the various cohorts as discussed
mortality with slightly higher adjusted hazard ratio’s (aHR), above identified potential risk factors for severe outcomes, as shown
17.3% (aHR 6.5) for primary AIHA and 30.9% (aHR 4.9) for in Table 1. In primary AIHA, mortality is associated with Evans
secondary AIHA. The one-year mortality for CAD/CAS in this syndrome, infections, renal failure and multi-treatment. Low
cohort was 14.5% (aHR 3.2) (32). Hazard ratios were even higher hemoglobin at onset (<8 g/dl) is a significant risk factor for ICU
in the first 100 days after AIHA diagnosis and decreased during admission, relapse and mortality. WAIHA with complement-
follow-up, still being significant for primary AIHA cases 10 years positive DAT, mixed AIHA and atypical AIHA are subtypes
after diagnosis (aHR 1.4), but not for secondary AIHA and CAD. associated with higher transfusion needs, multi-treatment and
Mortality in AIHA patients is frequently attributed to underlying hospitalisation. It is worth mentioning that, based on anecdotal
disease, but both the population-based studies show increased evidence and case reports, IgM warm AIHA (atypical AIHA, rare)
mortality even in primary AIHA (except for primary AIHA under are generally very severe and difficult to diagnose (often DAT
30 years), compared to a matched control group. In both studies, negative), and mainly show a dismal fulminant course (36–38).
the diagnosis of AIHA (and distinction of CAD/CAS), as well as The same can be said for IgA-only mediated AIHA, which can be
defining primary and secondary cases, is solely based on ICD easily missed as polyspecific DAT will often be negative. Several
codes in absence of (laboratory) data to confirm diagnosis. Since fulminant IgA-only cases with severe (intravascular) hemolysis
AIHA diagnostic criteria are complex, diagnosis registration have been reported (39–41).
might be incomplete and correlation with associated diseases
cannot be confirmed. Moreover, association with comorbidities
is highly variable, as AIHA can sometimes be the first symptom of Management of severe AIHA
the underlying disease, or underlying malignancies may manifest
after AIHA diagnosis (33). Indeed, in one study, underlying With the exception of one small clinical trial in severe
hematological malignancy was the most common cause of death complement mediated AIHA (42), there are no prospective
in the first year after diagnosis in secondary AIHA, but also intervention studies specifically focused on the severe AIHA
increased in primary cases (with adjusted hazard ratio of 10 subgroup. All recommendations on how to manage patients
versus comparators) (32). presenting with severe AIHA are therefore based on extrapolation
The Danish population-based cohort elaborated on causes of of treatment of AIHA in general and expert opinion. Recent
death in comparison to the general population (32). Anemia as a consensus on treatment of AIHA, with an emphasis on severe
cause of death was significantly higher in all AIHA subgroups cases, is summarized in Figure 1 (4, 43, 44).
during total study follow-up (>10 years). 2.8% of primary AIHA A full diagnostic work up is warranted, to establish the AIHA
cases died of cardiovascular causes within 100 days after diagnosis. subtype and confirm or rule out any underlying cause. If AIHA is
Mortality from cardiovascular disease was increased in all AIHA secondary, treatment of the underlying disease might be primarily
subgroups, and in primary AIHA and CAD, this increased risk indicated, or can guide the choice for AIHA treatment (45).
persists more than 10 years after diagnosis. This might reflect a However, in case treatment of the underlying disease is not
more complex interplay of hyperinflammation and (chronic) required or available, secondary AIHA could be treated as if
hemolysis leading to increased thrombotic risk, or side effects primary. Especially in severe cases, general AIHA treatment
from therapies (34). Other significantly increased causes of should not be delayed. Additionally, although of great
mortality were infections and bleeding. Increased risk of death by importance, incomplete diagnostic work-up as well should not
infections can be (partially) attributed to immunosuppressive delay any necessary treatment, including blood transfusions.
therapies, which are the cornerstone of AIHA treatment, Expert opinion on diagnostic testing is published elsewhere (4).
demonstrating the need for less immunosuppressive therapeutic Consultation of an expertise center is recommended for complex
options. Additionally, AIHA can be secondary to infections or cases with severe AIHA.

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TABLE 1 Potential risk factors for unfavorable outcome in AIHA.

Risk factor Outcome Source

Reticulocytopenia Life-threatening/fatal Case series. (8) Expert opinion. (4, 35)

Intravascular hemolysis (hemoglobinuria) Life-threatening/fatal Case series. (8) Expert opinion. (4, 35)

High indirect bilirubin at onset ICU admission AIHA cohort (23)

Low hemoglobin at onset (<8g/dl) ICU admission AIHA cohort (23)

Relapse/multiple treatment lines Primary AIHA cohort (12)

Mortality Primary AIHA cohort (18)

Serological type: wAIHA (IgG + complement), mixed, atypical. Need for transfusion Primary AIHA cohort (18)

Multiple therapy lines Primary AIHA cohort (12)

Hospitalisation Primary AIHA cohort (18)

Evans syndrome Mortality Primary AIHA cohort, case series (8, 12)

Infection Mortality Primary AIHA cohort (12)

Renal failure Mortality Primary AIHA cohort (12)

Multiple treatment lines Mortality Primary AIHA cohort (12)

Severe AIHA*

Supporve therapies
Clinical monitoring†
Transfusion
If (relave) reculocytopenia: ESA
LMWH prophylaxis
Folic acid

Diagnosc workup for secondary

Consider consultaon of or transfer Serological workup AIHA⸿: treat underlying disease if
to terary experse center
indicated

wAIHA Other variants‡ CAD

Consider steroids¥
Corcosteroids
Bridging therapies Bridging therapies Start rituximab
No response IVIg TPE#
aer 1 week TPE Complement inhibion

Add rituximab
Clone directed therapy
Rituximab-bendamusne
BTK inhibitors
Third line therapies Complement inhibion
Splenectomy Clinical trials
Other immunosuppressants¶ Sumlimab
Bortezomib Eculizumab

FIGURE 1
Algorithm for the management of severe AIHA. AIHA = autoimmune hemolytic anemia; ESA = erythropoiesis-stimulating agents; LMWH = low
molecular weight heparin; IVIg = Intravenous immunoglobulins; TPE = Therapeutic plasma exchange. Lower level of evidence in AIHA (see text). *
Typically, unstable hemoglobin <8g/dl and/or hemodynamic instability and/or transfusion interval <7 days. C Underlying diseases including, but not
limited to: hematological malignancies, infectious diseases, other auto-immune disease (SLE), primary immunodeficiencies (4). † Daily monitoring of
hemoglobin and hemolysis parameters. Consider monitoring in ICU. ‡ IgA AIHA, Mixed AIHA; rare and sometimes aggressive forms, typically
recommendations for wAIHA are followed, consultation of expertise center is indicated. ¥ High dose steroids may be effective in severe CAD cases.
Start tapering once rituximab has been started and discontinue in <6 months. # Therapeutic plasma exchange in CAD should occur at 37°C
(including extracorporeal circuit); exchange plasma for albumin and not donor plasma. ¶ i.e., mycophenolate mofetil, cyclophosphamide,
cyclosporin, azathioprine, danazol.

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A patient with confirmed or suspected severe AIHA should be transfusion (i.e., 1 unit/day) is preferred above multiple units at
admitted and monitored including (at least) daily hemoglobin and once (4).
hemolysis parameters. Unstable hemoglobin, reticulocytopenia,
symptomatic anemia, impending organ failure and/or other risk
factors as discussed above, should trigger hospitalisation for close Therapeutic strategies
monitoring until a stable clinical situation is achieved. There should
be a low threshold for ICU admission for intensive monitoring not In wAIHA in general, predniso(lo)ne (1mg/kg per day) is
limited to cases with organ failure. effective (~80%) and time to response is estimated at 7-25 days
(44). High dose intravenous methylprednisolone bolus at initiation
of therapy in acute cases is suggested, but solely based on experience
Blood transfusion in other autoimmune diseases. In CAD, steroids are ineffective
except for CAD patients at sustained high doses (0.7-1 mg/kg/day),
Similar as for other patients with anemia, the need for blood and may be considered for hemolytic crises, but should not delay
transfusion in AIHA patients is determined by the physician based more effective treatment options (43). In fact, rituximab (375 mg/
not only on hemoglobin levels, but also on clinical parameters as per m2 weekly for 4 weeks or 1000mg fixed dose bi-weekly) is the first
general guidelines. There is no consensus on a specific trigger for choice for CAD and is generally regarded as second choice for
transfusion in AIHA. In wAIHA and to a lesser extent in cAIHA, wAIHA patients, although time to response is 3-6 weeks. Early
the identification of possible alloantibodies during pretransfusion administration of rituximab is recommended in severe cases of
work-up can be challenging due to the presence of red blood cell CAD and wAIHA unresponsive to steroids (i.e., within 1 week),
reactive autoantibodies (usually pan-reactive). Additionally even though immediate effect is not anticipated.
required techniques to perform serological analysis are time
consuming and might warrant consultation of an expert
laboratory. Blood products may be selected that not only are Bridging therapies and supportive care
ABO and RhD matched, but also (depending on local facilities) Severe cases might rapidly deteriorate despite multiple blood
prophylactically matched for Rh phenotype (CcEe) and K to transfusions, while not (yet) responding to steroids, rituximab or
minimize alloantibody formation. In some transfusion guidelines, other therapeutic agents. In these situations, clinicians can resort to
blood products selected for AIHA patients are always Rh phenotype bridging therapies, such as intravenous immunoglobulins (IVIg) in
and K matched (46, 47). In 2/3rd of 115 transfused primary AIHA case of wAIHA or therapeutic plasma exchange (TPE). The
patients studied, RBC transfusions were effective (in this study, response (if response occurs) of both interventions is generally
defined as increment of 1 g/dl, stable for 3 days). Although, the quick (within days), but short-lived. Evidence for both interventions
efficacy was significantly lower in patients with Hb <6 g/dl is scarce, as efficacy for IVIg was only 32% in one small study, and
compared to Hb 6.1-8.0 g/dl (57% vs 75%), indicating less benefit use of TPE in AIHA is solely based on case series (55, 56). In case of
in more severe cases (12). General hesitance towards transfusion in CAD, TPE should occur at 37 °C and with albumin instead of donor
AIHA patients can be attributed not only to the complexity of pre- plasma, as colder temperatures and a new complement source could
transfusion testing but also the fear of adverse reactions because of potentially aggravate the disease.
positive crossmatches. Although this has been reported (48), in The addition of erythropoiesis-stimulating agents (ESA) such as
general transfusions in AIHA patients are well tolerated as several recombinant erythropoietin (rEPO), may be beneficial based on
(small) cohorts found no hemolytic transfusion reactions (49–51). retrospective data, especially when there is (relative)
Moreover, the inflamed state of AIHA patients might make them reticulocytopenia (57). This supportive treatment may be
more susceptible to develop alloantibodies, mainly of Rh specificity underutilized, as nearly all (92%) ICU-admitted patients in the
(52). Given the arguments presented above, despite limited French cohort had inadequate reticulocytosis, and only 20%
evidence, it is reasonable to minimize the use of transfusions in received ESA (23).
AIHA patients. However, for vital indications (severe anemia < 6g/ Thrombosis and infection are known complications in AIHA
dl, cardiovascular risk factors) blood transfusions should not be and among the leading causes of death (58, 59). Even though
withheld, and in case of hypoxemia symptoms, administered thrombotic events were not significantly associated with fatal
without delay, even if pre-transfusion work-up is incomplete. outcome in the largest cohort, AIHA is associated with increased
Timely communication between clinicians, immunohematology thrombotic risk and cardiovascular mortality (32, 60–62).
laboratory and transfusion service is essential for appropriate Predictors for thrombotic risk are not fully clarified, but may be
work-up and preventing undesired transfusion delay (52). In case warm and mixed AIHA, and active and intravascular hemolysis (58,
of incompatible blood products, it makes sense to start steroids 59). Therefore, thrombosis prophylaxis is strongly advised,
before the first unit is transfused, if possible, since this may lower especially in hospitalized patients with severe anemia and LDH
the risk of alloantibody formation (53). In cAIHA patients, blood >1.5 times upper limit of normal, and/or additional risk factors for
products should be administered with use of a blood warmer. thrombosis (i.e., antiphospholipid syndrome) (4). There are no
Although only based on expert opinion, the rationale is in line infectious prophylaxis guidelines for AIHA. Awareness of infection
with widely accepted recommendations (4, 46, 54). For adequate risks is important, and prophylaxis can be considered in individual
monitoring of efficacy and 281 hemolysis stability, regular cases based on local guidelines (63).

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New therapeutic developments inhibitors are approved for B-cell lymphoproliferative neoplasms
A proportion of patients deteriorate despite currently available and are increasingly studied in autoimmune disorders.
therapies. Indeed, there is a lack of effective, rapidly acting agents to Retrospective data shows ibrutinib (first generation BTK
halt the massive hemolytic activity in severe AIHA. Complement inhibitor) was effective in 90% of cAIHA patients (n=15, 4 CAD,
inhibitors are emerging in complement-mediated AIHA (typically 11 CAS). All 11 transfusion-dependent patients became
cold antibody AIHA and, to some extent, wAIHA with complement transfusion-independent of whom 9 within 1 month (77). In a
positive DAT). Several phase II-III trials of C1 inhibition in CAD pilot study of ibrutinib in 2 cases with relapsed/refractory primary
have shown favourable results (64–66). This had led to the approval wAIHA, both cases showed response and were transfusion
of the C1s inhibitor sutimlimab by FDA and EMA for the treatment independent within 2 weeks (78). An open-label phase I-II trial
of CAD (67, 68). However, there currently are no data on studied rilzabrutinib (second generation BTK inhibitor) in patients
sutimlimab in the setting of severe complement-mediated AIHA. with immune thrombocytopenia (ITP), an immune cytopenia
A small pilot phase II study on peri-transfusional administration of similar to AIHA. The BTK inhibitor was effective in 40% of the
plasma derived C1 inhibitor in severe complement mediated AIHA patients, and a majority showed improved platelet counts within 2
showed negative results, despite a significant decrease of C3d weeks (79). Currently, a phase II trial with ibrutinib is recruiting
deposition on RBCs (42). Studies with various other proximal participants with relapsed/refractory warm or mixed AIHA (80). A
complement inhibitors are ongoing (69–71). Pegcetacoplan, a C3 phase II trial with zanubrutinib (second generation BTK inhibitor)
inhibitor, has shown effective and is approved for paroxysmal in CAD has been announced (81).
nocturnal hemoglobinuria (PNH). A phase III trial in primary An alternative approach to reduce antibody mediated hemolysis
AIHA (both CAD and wAIHA) is ongoing. Preliminary results of in wAIHA, is through inhibition of spleen tyrosine kinase (SYK)
an earlier phase II trial indicate a higher efficacy in CAD compared signaling. The inhibition of SYK-dependent signaling of Fcg
to wAIHA with complement positive DAT, and suggest no effect in receptors on macrophages and BCR on B cells is thought to
wAIHA with complement negative DAT (72). Eculizumab, a reduce phagocytosis and pathogenic antibody production. In a
terminal C5-inhibitor also approved for PNH, had an effect on phase II trial in wAIHA, fostamatinib was effective in 46% of
hemolysis and decreased transfusion needs in CAD patients in one wAIHA patients. Responses were seen within 2 weeks of
prospective clinical trial. However the effect was modest, most likely initiation. A large (n=90) placebo controlled phase III trial
due to ongoing C3-mediated extravascular hemolysis (73). however, did not meet the predefined primary endpoint (82).
Although limited data are available in severe CAD, a theoretical Persisting CD20 negative long-lived autoreactive plasma cells
benefit from C5 inhibition, preventing intravascular hemolysis via are suggested as a possible explanation for refractoriness to
the membrane attack complex (MAC) route, could be of added rituximab (CD20 monoclonal antibody) The proteasome inhibitor
value in fulminant cases. This has led to recommendations for using bortezomib has multiple immunomodulatory effects and is used for
eculizumab in these severe cases (4), but this hypothesis needs its proapoptotic effect on plasma cells. Its potential has been
further study. Moreover, the overwhelming complement activation demonstrated in several case reports of relapsed/refractory
in severe cases might ask for higher or more frequent dosing. wAIHA, with median time to response of 2 to 3 weeks (83). One
Therefore, while complement inhibitors are potentially very prospective trial in cAIHA was conducted, with an overall response
effective in halting hemolysis in fulminant complement mediated rate of 32% after 3 months in a heavily pre-treated group of cAIHA
AIHA, their exact efficacy and optimal dosing in this setting patients (84). Whether some responses were quicker is not reported.
remains to be determined. An alternative approach to deplete long-lived autoreactive plasma
Not all severe AIHA patients would benefit from complement cells, are monoclonal antibodies targeting CD38 (highly expressed
inhibitors, since hemolysis is not primarily complement driven in in plasma cells), such as daratumumab. Daratumumab is approved
the majority of wAIHA. Furthermore, complement inhibition does for the treatment of multiple myeloma. Retrospective data suggests
not reduce the pathogenic antibody production, and would a potential role in warm and cold AIHA, mainly described in the
presumably be a life-long treatment in the majority of cases. context of post allogeneic bone marrow transplantation. The
Indeed, several other agents are explored in clinical trials for majority of responses occurred within 2 weeks. A phase I trial in
AIHA, mainly for relapsed and refractory cases. Some of these relapsed/refractory AIHA is currently recruiting and a phase Ib/II
agents might have potential in the acute setting, depending on time study with isatuximab, an analogue, in wAIHA is currently ongoing
to response (74). (85, 86).
Phosphoinositide 3-kinases (PI3K) are involved in cell Finally, nipocalimab, an FcRn blocker, has the potential to
metabolism and survival and delta isoforms are selectively induce a quick response, as serum IgG autoantibodies decreased
expressed in hematopoietic cells, crucial for B-cell development within 8 days in a phase II trial in Myasthenia gravis (87). A clinical
and proliferation. Parsaclisib, a PI3Kd inhibitor, achieved a (partial trial with nipocalimab in wAIHA is currently ongoing (88).
or complete) response in 64% (even 75% in wAIHA subgroup) in a In summary, numerous strategies for the treatment of refractory
phase II trial (n=12), with hemoglobin levels improving within 2 and relapsed AIHA cases are explored, with varying success rates.
weeks (75). A phase III trial in wAIHA is currently ongoing (76). The various targets illustrate the diversity of AIHA pathophysiology
Bruton’s tyrosine kinase (BTK) plays an important role in B-cell and the moderate success rates in some studies might represent our
activation and Fcg receptor signalling in macrophages. BTK incomplete understanding of AIHA pathophysiology and

Frontiers in Immunology 07 frontiersin.org

Mulder et al. 10.3389/fimmu.2023.1228142

predictors for the most effective strategy in each individual case. It is efficacy and optimal dosing of (novel) therapeutic agents, especially
important to highlight the lack of inclusion and/or (sub)analysis of focussing on strategies that may rapidly abrogate hemolytic activity.
severe AIHA patients, as this population might require different
dosing or preferred targets than a chronic, less severely hemolytic
AIHA subgroup. Author contributions
FM and JV wrote the first draft of the manuscript. All authors
Conclusions and knowledge gaps equally added critical discussions throughout the writing of the
manuscript. All authors reviewed and approved the submitted version.
AIHA is a heterogenous disease, and a substantial subgroup is at
risk for hospitalisation, transfusion dependency and complications.
The risk for ICU admission is uncertain, but mortality of AIHA Funding
patients in the ICU is high. All AIHA patient groups, apart from
primary AIHA under 30 years, have increased mortality compared The authors declare that this study received funding from
to the general population. Causes of death include cardiovascular Sanquin Diagnostics B.V. Unit Healthcare. Grant number PPO-
disease, infections and anemia itself. Survival of AIHA patients has SHS-2022-22.13/L2687. The funder was not involved in the study
only modestly improved since 1980 (32) and increased mortality in design, collection, analysis, interpretation of data, the writing of this
both primary and secondary cases emphasizes that development of article, or the decision to submit it for publication.
novel therapeutic options for AIHA is still pertinent.
Some patients may deteriorate rapidly with deep anemia due to
uncontrolled hemolysis, but data on the incidence and outcomes of Conflict of interest
severe AIHA is lacking. This knowledge gap impairs the recognition
of patients at risk for severe disease course as well as improvement MH and JV were employed by Sanquin Diagnostic Services.
of management strategies. Future research, on the one hand, should MH discloses consultancy for Johnson and Johnson and Omnia
focus on validating risk factors for severe AIHA incorporating education. WB discloses consultancy and advisory board
clinical characteristics but also immunological variables. involvement with Agios, Alexion, Incyte, Novartis, and Sanofi, as
Development of diagnostic scores ask for large prospective cohort well as research support provided by Alexion. BF declares receiving
studies incorporating consensus-based definitions of severe AIHA. consultancy honoraria from Alexion and Janssen, as well as
A comprehensive understanding of the pathophysiology, clinical participating in the speakers' bureau for Alexion and Sobi. JV has
course and outcomes of severe AIHA is crucial to identify unmet declared receiving consultancy and advisory board honoraria from
needs in its management. Although improved protocols for Sanofi and Janssen, research support from Beigene and Abbvie/
supportive care, such as thrombosis and infection prophylaxis, may Genmab, and participating in the speakers' bureau for BMS, Sanofi,
be advantageous, the evidence to support such protocols is limited. and Amgen. All honoraria received are directed to the institute.
Transfusion triggers are unclear, and the risk and benefits of The remaining authors declare that the research was conducted
transfusion in this setting are also to be elucidated. With new in the absence of any commercial or financial relationships that
targeted therapeutic options becoming available, treatment could be construed as a potential conflict of interest.
algorithms should go beyond differentiating between warm and
cold AIHA and consider immunological markers, underlying
diseases, and clinical parameters to guide the timing and order of Publisher’s note
therapeutic agents. Currently, the lack of knowledge on severe AIHA
and clinical trials in this subgroup, obstruct the development of All claims expressed in this article are solely those of the authors
evidence-based treatment guidelines for severe cases. Rapidly effective and do not necessarily represent those of their affiliated organizations,
therapies are lacking, and although new therapies emerge, their or those of the publisher, the editors and the reviewers. Any product
potential in acute hemolytic crises is unsure. There is a need for that may be evaluated in this article, or claim that may be made by its
prospective clinical trials in the subset of severe AIHA, to evaluate the manufacturer, is not guaranteed or endorsed by the publisher.

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