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Cold agglutinin disease

Cold agglutinin disease
Authors:
Carlo Brugnara, MD
Sigbjørn Berentsen, MD, PhD
Section Editor:
Robert A Brodsky, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Jul 25, 2022.

INTRODUCTION — Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia (AIHA) in which cold agglutinins (IgM autoantibodies against red blood cell [RBC] antigens with an optimum temperature of 3 to 4°C) can cause clinical symptoms related to RBC agglutination in cooler parts of the body and hemolytic anemia.

This topic will review the pathophysiology, clinical manifestations, diagnosis, and treatment of CAD.

Warm AIHA and other cold-related hematologic disorders are discussed in separate topic reviews:

Warm AIHA (immune hemolysis at normal body temperature) – (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Paroxysmal cold hemoglobinuria (intravascular hemolysis due to a cold-sensitive antibody) – (See "Paroxysmal cold hemoglobinuria".)

Cryoglobulinemia (immunoglobulins that precipitate in the cold; not associated with hemolysis) – (See "Overview of cryoglobulins and cryoglobulinemia".)

TERMINOLOGY AND DISTINCTION AMONG SYNDROMES — There are three major types of cold-sensitive antibodies that can cause clinical manifestations: cold agglutinins (which cause CAD), Donath-Landsteiner antibodies (which cause paroxysmal cold hemoglobinuria [PCH]), and cryoglobulins (which cause a vasculitic picture):

Cold agglutinins – Cold agglutinins are antibodies that recognize antigens on red blood cells (RBCs) at temperatures below normal core body temperature. They can cause agglutination of the RBCs (picture 1) and extravascular hemolysis, resulting in anemia, typically without hemoglobinuria.

Cold agglutinins may be seen with the primary cold agglutinin disease (CAD) or secondary cold agglutinin syndrome (CAS) [1-3]. The antibodies are typically immunoglobulin M (IgM) and the antigen is typically "I" or "i" on the RBC surface.

Primary CAD – Primary CAD (also called idiopathic CAD) is used to refer to cold agglutinins that cause RBC agglutination and extravascular hemolysis in the absence of an underlying disorder. As discussed below, these individuals are thought to have a low-grade clonal bone marrow disorder [4]. (See 'Cold agglutinins' below.)

Secondary CAS – When cold agglutinins arise in the setting of an underlying disorder such as a viral infection, autoimmune disorder, or lymphoid malignancy, the syndrome is referred to as secondary CAS. (See 'Associated disorders' below.)

Donath-Landsteiner antibodies – Donath-Landsteiner antibodies are antibodies that recognize RBC antigens at cold temperatures, but unlike cold agglutinins, these antibodies fix complement and cause hemolysis in the circulation (intravascular hemolysis). This is why patients have symptoms associated with hemoglobinemia and hemoglobinuria (eg, flank pain, dark urine). This condition is called paroxysmal cold hemoglobinuria (PCH). The antibodies are usually IgG and they are often directed against the "P" antigen on RBCs. (See "Paroxysmal cold hemoglobinuria".)

Cryoglobulins – Cryoglobulins are antibodies that form immune complexes in the cold; they generally do not interact with RBCs. Cryoglobulins can cause a systemic vasculitis, a systemic inflammatory syndrome, or vascular occlusion. (See "Overview of cryoglobulins and cryoglobulinemia".)

The clinical features associated with the above disorders are summarized in the table (table 1).

The antibodies may share some clinical features. As examples:

They may occur after infections or in the setting of lymphoproliferative or autoimmune disorders

They can all cause Raynaud phenomenon

Although cryoglobulins do not cause anemia directly, they may be associated with inflammatory or neoplastic disorders that cause anemia

Rarely, antibodies may act as both cold agglutinins and cryoglobulins

PATHOGENESIS

RBC antigens — There are a variety of antigenic epitopes on the surface of red blood cells (RBCs), many of which have been serologically defined as blood group antigens. Cold agglutinins react with RBC antigens that contain polysaccharide epitopes on glycoproteins or glycolipids such as ceramide or glycophorins.

The vast majority of cold agglutinins are directed against "I" or "i" antigens of the I blood group (referred to as "big I" or "little i" respectively). (See "Red blood cell antigens and antibodies", section on 'Lewis, P1P(K), GLOB, and I blood group systems'.)

The big I and little i antigens are ubiquitous (present on all cell membranes) and structurally related [5-7]. Little i is the predominant structure on fetal RBCs. It consists of a straight-chain polymer of at least two lactosamines. After birth, an enzyme becomes activated that can add additional lactosamine disaccharides to galactose, resulting in a branched chain structure that constitutes the big I antigen. Thus, little i is progressively converted to big I during infancy, and most children become big I positive by the age of two years. The function of the big I and little i antigens is unknown.

Big I is present on RBCs in the vast majority of the population (approximately 99 percent)

Little i is present on RBCs in less than 1 percent of the population; these individuals are also called "big I negative"

In certain settings, the antigen may be associated with a specific infectious cause of cold agglutinin production (usually the I antigen in Mycoplasma pneumoniae infection and the i antigen in infectious mononucleosis) (table 2). However, the antigenic target of the cold agglutinin cannot be used to distinguish among any underlying conditions.

These complex polysaccharides also serve as precursors for the assembly of the ABO and Lewis blood group antigens. Sometimes, the epitope of particular anti-I or anti-i antibodies may include parts of the ABO or Lewis antigens. The specificity of these antibodies is designated anti-IA, anti-IB, etc. Rare antibodies react equally well with the I and the i structure; these antibodies are designated "anti-j."

Less commonly, antibodies have been described that react with RBCs that have been treated with proteases (referred to as "anti-Pr") or with sialidase. Those that are dependent upon sialic acid (which may be added to the end of the complex polysaccharide structures) are designated "Sia" followed by an "l" if on the linear (i-like structure), a "b" if on the branched (I-like structure), or both if on both structures. As an example, Sia-l would designate a sialic acid-dependent structure on the linear polysaccharide. These sialic-acid dependent antibodies are rare.

Cold agglutinins — Cold agglutinins are autoantibodies directed against RBC antigens. They have the following properties:

Isotype – The vast majority of cold agglutinins are IgM [8]. IgA or IgG cold agglutinins have occasionally been reported, although IgA cold agglutinins probably do not result in CAD [9-13]. IgM antibodies are pentameric, which places antigen-binding sites sufficiently far apart to allow them to bridge the distance between RBCs. This binding of multiple RBCs by the same IgM molecule is the basis for agglutination by these antibodies. Even a small amount of antibodies, perhaps as few as 25 per RBC, can produce obvious agglutination [14].

Light chain – In CAD, cold agglutinins are more likely to have kappa than lambda light chains. In a large cohort of patients with CAD from Norway, 94 percent of cold agglutinins had kappa light chains [11].

Specificity – The vast majority of cold agglutinins are either anti-I or anti-i, as discussed above (see 'RBC antigens' above). These different antibodies and their properties are summarized in the table (table 2). Specificity can be determined using serologic methods, although this is not required for routine management other than transfusion. Previously, the specificity was inferred based on whether the antibodies were more effective at agglutinating RBCs from adults or from umbilical cord blood [15].

Titer – As noted above (see 'Terminology and distinction among syndromes' above), the titer is the number of dilutions after which the antibody can still cause agglutination; it reflects antibody concentration and avidity. Generally, a titer ≥64 is considered clinically significant. (See 'Antibody titer and thermal amplitude' below.)

Thermal amplitude – As noted above, cold agglutinins react with RBCs at colder temperatures than normal core body temperature. The temperature range at which they are active is referred to as the thermal range or thermal amplitude. The typical thermal amplitude for normally occurring cold agglutinins is in the range of 3° to 4° C (ie, refrigerator temperature), but many antibodies are active at higher temperatures such as occur in colder, acral areas of the body [8]. Antibodies that cause agglutination only at refrigerator temperature may cause agglutination in vitro but are unlikely to cause clinical disease. (See 'Antibody titer and thermal amplitude' below.)

Clonality – Cold agglutinins can be monoclonal (derived from a single clone of lymphocytes; having a single, uniform epitope specificity) or polyclonal (derived from multiple independent lymphocytes; having multiple epitope specificities). Monoclonal cold agglutinins are typically associated with lymphoproliferative disorders, and they are more pathogenic than polyclonal cold agglutinins [16].

Most cases of primary CAD are thought to originate from a low-grade lymphoproliferative disorder and thus to be monoclonal. Implicated mutations such as those in the KMT2D and CARD11 genes are discussed below. (See 'Primary CAD-associated lymphoproliferative disorder' below.)

Most cases of secondary cold agglutinin syndrome (CAS) associated with a lymphoid malignancy are monoclonal, and most cases of secondary CAS associated with a viral infection are polyclonal [8].

For therapy, monoclonal cold agglutinins generally require systemic agents to eradicate the B-cell clone that is producing them (see 'Therapies directed at the pathogenic process' below); polyclonal cold agglutinins associated with infections resolve spontaneously in most cases.

Molecular characterization of cold agglutinins has demonstrated other features of their structure. As an example, most cold agglutinin heavy chains appear derived from a restricted set of variable domains. Out of approximately 100 possible V(H) genes available, nearly all antibodies of I, i, or j (I and i) specificity use a single V(H) gene (IGHV4-34; formerly called VH4-21) [17-21]. Monoclonal IGHV4-34 gene rearrangement was also seen in eight of eight samples from the bone marrow study discussed below [22] (see 'Primary CAD-associated lymphoproliferative disorder' below). This may make them easier to identify in the laboratory. The IGHV4-34variable region is also used by clinically important IgM antibodies against other antigens such as other blood group antigens, DNA (in systemic lupus erythematosus [SLE]), and endotoxin [23-25]. Additional studies using mutagenesis or crystallography have determined the specific amino acid residues responsible for binding to polysaccharide antigens [26,27].

Cold agglutinins bind weakly to RBCs at temperatures approaching body temperature and more strongly at lower temperatures. This is because the binding of cold agglutinins to the carbohydrate antigens such as "I" and "i" occurs predominantly through weak bonds such as hydrogen bonds and van der Waals forces rather than through ionic bonds. This weak reaction may be due to the nature of both the antigen and the antigen-binding site on the antibody, both of which are very restricted in their chemistry. These weak forces are made stronger by reduction in ambient temperature, which has the effect of reducing spontaneous Brownian movement; this feature of binding accounts for the cold-reactivity of cold agglutinins. This property of certain antibodies associated with hemolytic anemia that caused them to have a strong interaction with RBCs below core body temperature was the basis for the original description of these antibodies as cold agglutinins [28].

Primary CAD-associated lymphoproliferative disorder — As noted above, cold agglutinin-mediated AIHA can occur in the setting of an underlying viral infection, autoimmune disorder, or lymphoid malignancy, referred to as secondary cold-agglutinin syndrome, or without one of these underlying disorders, referred to as primary CAD. (See 'Terminology and distinction among syndromes' above.)

Despite the lack of an underlying malignancy, most cases of primary CAD produce a monoclonal cold agglutinin, suggesting a clonal proliferation of cells from a lymphoproliferative disorder. The term "CAD-associated lymphoproliferative disease" has been proposed to describe this entity [4,20]. Previously, we referred to it as a "benign monoclonal variant" to distinguish it from overt lymphoma or other lymphoproliferative disorders. In 2022, CAD was recognized as a distinct lymphoid neoplasm in the World Health Organization (WHO) classification of hematolymphoid neoplasms [29,30].

The nature of this lymphoproliferative disorder was investigated in a study in which 54 individuals with CAD who did not have evidence of an extramedullary lymphoma (ie, none had lymphadenopathy, splenomegaly, or abnormal lymphocytes in the peripheral blood) had their bone marrow samples analyzed by a group of pathologists using a standardized panel of flow cytometry, immunohistochemistry, and mutational analysis (picture 2) [22]. Major findings included the following:

The most common morphologic finding was a lymphoid infiltration of nodular B-cell aggregates, seen in 40 of the 54 (74 percent); the remaining 14 had scattered B cells (picture 2). Mature plasma cells were sometimes seen surrounding the aggregates as well as throughout the bone marrow, but the number of plasma cells generally was not increased (range, 2 to 10 percent of nucleated cells). Immunophenotyping demonstrated that the lymphocytes were mostly B cells expressing IgM with a kappa light chain, and the plasma cells expressed IgM with kappa light chains. The predominant immunophenotype was positive for CD19, CD20, CD22, CD79b, and FMC7; CD23 was negative and CD5 was seen in less than half of the cases. In the 14 individuals who did not have lymphoid aggregates, flow cytometry on blood or bone marrow demonstrated a monoclonal population of B cells with similar features.

In contrast to lymphoplasmacytic lymphoma (LPL; the underlying bone marrow finding in Waldenström macroglobulinemia), there was no characteristic LPL morphology; there was no increase in mast cells, paratrabecular growth, or fibrosis; and the testing for the MYD88 L265P mutation, commonly seen in LPL, was negative in all 17 cases tested. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

Although the immunophenotype was similar to extranodal or nodal marginal zone lymphoma, none of the patients had extramedullary disease.

Separate studies evaluating genetic changes have found the following:

Exome sequencing or targeted sequencing of selected genes in B cells isolated from the bone marrows of 16 individuals with primary CAD using exome sequencing of bone marrow-derived B cells in six and targeted sequencing of selected genes in the remaining 10 identified variants in KMT2D in 11 (69 percent) and variants in CARD11 in five (31 percent); four of these also had a KMT2D variant [4]. Inactivating KMT2D mutations are also seen in certain lymphomas. Use of histone deacetylase (HDAC) inhibitors in the treatment of these lymphomas, as well as in Kabuki syndrome (germline pathogenic variant in the KMT2D gene) is under study.

Cytogenetic analysis of 15 samples of bone marrow-derived B cells identified complete or partial gain of chromosome 3 in 14 (93 percent), along with gain of chromosome 12 or 18 in 11 (73 percent) [31]. These changes are similar to those seen in marginal zone lymphoma (MZL). Although numbers were small, chromosome 18 gains appeared to be associated with decreased response to therapy, also similar to MZL.

The likelihood of progression to a malignant lymphoid neoplasm is unknown, but in most cases, the cold agglutinin persists without change for a number of years. The frequency of transformation to an aggressive lymphoma is very low (probably 3 to 4 percent over 10 years) [11,32].

Mechanism of hemolysis — Hemolysis in CAD is primarily extravascular and mediated by complement. The following sequence of events is thought to be most typical [16,33,34]:

The IgM cold agglutinin binds to its cognate antigen (usually "I" or "i") on the surface of RBCs in sites of the body where the temperature is low enough to be in the thermal range of the antibody (eg, acral areas, especially with cold ambient temperatures). (See 'RBC antigens' above and 'Cold agglutinins' above.)

The bound IgM recruits components of the classical pathway of complement, such as C1, C4, and C2 [35]. (See "Overview and clinical assessment of the complement system", section on 'Pathways and activating conditions'.)

C1-esterase activates C4 and C2, leading to production of the C3 convertase, which cleaves C3 to C3a and C3b, as illustrated in the figure (figure 1). (See "Complement pathways", section on 'Classical pathway'.)

C3b-coated RBCs are phagocytosed by macrophages in the reticuloendothelial system (ie, extravascular hemolysis), predominantly Kupffer cells in the liver [36]. (See "Diagnosis of hemolytic anemia in adults", section on 'Extravascular hemolysis'.)

Phagocytes tend to engulf the entire cell rather than a portion of the cell membrane, as occurs in phagocytosis mediated by IgG. This may explain the absence of spherocytosis in CAD (or a relatively less impressive spherocytosis), compared with warm autoimmune hemolytic anemia (AIHA). (See 'CBC, blood smear, and hemolysis testing' below.)

On the remaining circulating RBCs (ie, those that are not phagocytosed), IgM dissociates upon warming, but C3b remains attached. Surface C3b undergoes cleavage to C3d, which can be detected by the direct antiglobulin (Coombs) test [34]. A positive Coombs test for complement is one of the initial findings that suggests CAD, as discussed below. (See 'CBC, blood smear, and hemolysis testing' below.)

Typically, complement inhibitors such as CD55 and CD59 on the RBC surface prevent the classical complement pathway from activating the terminal cascade, in which the membrane attack complex (MAC; C5b-9) lyses the cells intravascularly. However, when hemolysis is especially brisk (eg, with concomitant infection, surgery, or other inflammatory states), a component of intravascular hemolysis may occur [34]. In these cases, patients may have hemoglobinuria, which occurred in 15 percent of patients in one series [33]. In other rare cases, an IgG antibody may accompany the IgM cold agglutinin (so-called "mixed" autoimmune hemolytic anemia); this may lead to more severe hemolysis including an intravascular component [37,38]. (See 'CBC, blood smear, and hemolysis testing' below.)

Studies of the in vitro properties of cold agglutinins in several patients with CAD have determined that the severity of hemolysis correlated most closely with properties of the antibody (eg, avidity for RBC membrane, ability to fix complement, thermal amplitude) rather than cold agglutinin titer [15,36,39,40].

EPIDEMIOLOGY — Primary CAD is a rare disease. In retrospective reviews from Nordic countries, the incidence has been estimated at approximately 1 to 1.8 per million and the prevalence at approximately 13 to 16 per million [11,41]. A series that included nearly all affected individuals in Norway and Lombardy (North Italy) found prevalences of approximately 20 per million and 5 per million, respectively, suggesting a four-fold higher prevalence in colder climates (mean temperature in Norway, 7° C colder than North Italy) [32].

Studies have also demonstrated a slightly higher prevalence in females and a median age of diagnosis in the late 60s to early 70s. (See 'Clinical manifestations' below.)

CAD is significantly less common than warm autoimmune hemolytic anemia (warm AIHA), accounting for approximately one-fifth to one-quarter of patients with AIHA in retrospective series [38,42].

The prevalence of secondary cold agglutinin syndrome in individuals with underlying infection or lymphoid malignancies has been estimated from various case series. As examples:

In a series of 496 individuals with M. pneumoniae infection in Denmark, 407 (82 percent) had in vitro evidence of cold agglutinins; however, these were not associated with clinical symptoms or hemolysis, and it is likely that the majority of cold agglutinins were clinically silent [43].

In a series of 217 individuals with Waldenström macroglobulinemia, 5 percent had cold agglutinins, but only 1.5 percent had hemolysis [44].

ASSOCIATED DISORDERS — The likelihood that a person with cold agglutinin-mediated AIHA has an underlying disorder depends on their age and the extent of the evaluation performed. Younger patients may be more likely to have an underlying infection or autoimmune disorder, and older individuals (eg, >60 years of age) may be more likely to have a lymphoid (B-cell or plasma cell) malignancy such as aggressive non-Hodgkin lymphoma or Waldenström macroglobulinemia (WM).

There is also a sizeable group of patients with no evidence of lymphoma who have a monoclonal cold agglutinin. Most if not all of these individuals probably have a low-grade lymphoproliferative disorder responsible for the production of a monoclonal cold agglutinin [45]. (See 'Primary CAD-associated lymphoproliferative disorder' above.)

Although cold agglutinins have been reported in individuals with solid tumors, this likely represents an incidental association rather than a causal relationship [46].

Infections and autoimmune disorders — Cold agglutinins regularly occur during the course of two infections:

M. pneumoniae (primary atypical pneumonia) [47-49]

Epstein-Barr virus (infectious mononucleosis) [50]

Case reports have described cold agglutinins in the setting of other viral infections such as HIV, rubella virus, influenza viruses, COVID-19 infection, or varicella-zoster virus (chickenpox) [43,51-54].

Not all individuals with these infections who develop cold agglutinins will have clinically significant hemolysis. For those who do, it usually occurs approximately two weeks after onset of the primary infection, diminishes as the infection begins to resolve, and is gone within two to three months.

Cold agglutinins have also been described in individuals with autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis [55,56].

Lymphoid malignancies — The association with B-cell or plasma cell lymphoproliferative disorders has been illustrated in several case series. As examples:

In a 2006 series of 78 individuals with persistent cold agglutinins (average age, over 60 years), associated lymphoid malignancies were present in approximately 65 percent [57]:

Lymphoma – 31 (40 percent)

Waldenström macroglobulinemia (WM) – 13 (17 percent)

Chronic lymphocytic leukemia (CLL) – 6 (8 percent)

In a 2013 series of 89 patients with CAD (median age, 65 years), lymphoid disorders were present in approximately 78 percent [33]:

Monoclonal gammopathy of undetermined significance (MGUS) – 42 (47 percent)

Other non-Hodgkin B-cell lymphoma – 8 (9 percent)

Unspecified lymphoproliferative disorder – 8 (9 percent)

CLL – 4 (4 percent)

Earlier case series showed similar findings [57]. In light of subsequent studies, a majority of these cases would be classified as having "CAD-associated lymphoproliferative disorder" [22,32].

Whenever the cold agglutinin is the result of malignant proliferation, its concentration in the plasma may be used as a tumor marker. The antibody may disappear with appropriate treatment and reappear with relapse of the tumor.

CLINICAL MANIFESTATIONS

Overview of typical findings — The mean age at presentation of CAD is in the mid to late 60s, with a broad range (30s to 90s) [11,32,33].

In many cases, individuals with circulating cold agglutinins may be unaware of the presence of these antibodies unless or until they are exposed to cold temperatures that enhance antibody binding to red blood cells (RBCs). In countries with cool or temperate climates, CAD is diagnosed more frequently during the cold seasons [58].

However, when the disease is diagnosed, clinical and hematologic manifestations seem to persist year-round [59]. Cases of catastrophic hemolysis and organ failure have been described in cardiac surgery involving hypothermia (eg, for cardiopulmonary bypass) [60]. On the other hand, it is important to emphasize that not all individuals with demonstrable cold agglutinins have a cold agglutinin-related disease. In one series, for example, cold agglutinins were found in 0.3 percent of individuals with unrelated disorders [61].

The largest published series, involving 232 affected individuals, reported the following likelihoods of common findings [32]:

Anemia (median hemoglobin, 9.5 g/dL) – 90 percent (compensated hemolysis in the remainder)

Hemolytic markers (high lactate dehydrogenase [LDH] and bilirubin, low haptoglobin) – approximately 90 percent each

Cold-induced symptoms (mostly acrocyanosis) – 52 percent

More severe cold-induced symptoms such as Raynaud phenomenon or ulceration were seen in a smaller proportion. Fatigue is a well-recognized symptom that may be caused by the anemia as well as by complement activation alone, although the exact frequency is unknown [62]. Transfusions were given, either preceding diagnosis or during follow-up, in 38 to 47 percent [32]. During follow-up, 3.4 percent developed diffuse large B cell lymphoma (DLBCL). (See 'Lymphoid malignancies' above.)

Cold-induced symptoms (eg, acrocyanosis and Raynaud phenomenon) — Cold-induced symptoms in the acral areas are extremely common in CAD, affecting over 90 percent of individuals who live in colder climates such as in Scandinavia [11,32]. These symptoms can range from mild to disabling and include the following:

Acrocyanosis (dark purple-to-gray discoloration of the skin in acral areas such as fingertips, toes, nose, and ears)

Livido reticularis (a blanchable, patchy, reticulated vascular pattern on the skin with a red-blue or violaceous color) (picture 3)

Raynaud phenomenon (sharply demarcated color changes of the skin of the digits) (picture 4)

Cutaneous ulceration or even necrosis in severe cases [63-66]

Pain or discomfort on swallowing cold food or liquids

As noted above, these symptoms are related to RBC agglutination by IgM that bind to their surface in the cold (see 'Cold agglutinins' above). They disappear upon warming, and there is often little or no reactive hyperemia that is sometimes seen in the reperfusion phase of Raynaud phenomena. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Clinical features'.)

Hemolytic anemia (Coombs-positive for complement) — Hemolysis (extravascular) is common in CAD. The severity can range from compensated hemolysis without anemia to severe hemolytic anemia requiring transfusion [8,32]. Some individuals have chronic compensated hemolytic anemia with episodes of more severe anemia due to increased hemolysis precipitated by cold temperatures or inflammatory responses.

Episodes of hemolysis may be precipitated by exposure to colder ambient temperatures, as illustrated in a case report of a road worker with CAD who was outside during the days and had clearly documented seasonal hemolysis [67].

Episodes of hemolysis may also be exacerbated by febrile or other acute illnesses, as illustrated in a one-year prospective study of an individual who was generally in good health but developed hemolysis several times during a one-year period of observation that correlated with episodes of the common cold, pneumonia, and hip fracture [68]. A study of 15 individuals with chronic CAD found hemolysis during episodes of fever in five (one-third) participants.

Median hemoglobin levels in the larger case series are approximately 9 to 10 g/dL, with some individuals in the normal range and others as low as 4.5 g/dL [11,32,33]. In a large series of 232 individuals, 25 to 30 percent had a hemoglobin <8 g/dL [32].

Symptoms attributable to anemia may occur, often in proportion to the severity of the anemia and the rapidity of its development. These may include exertional dyspnea, dyspnea at rest, varying degrees of fatigue, and signs and symptoms of the hyperdynamic state. Some individuals may develop jaundice or mild splenomegaly related to hemolysis.

Laboratory findings are consistent with autoimmune, extravascular hemolysis mediated by the classical complement activation pathway. (See 'CBC, blood smear, and hemolysis testing' below.)

Fatigue — Many patients with CAD experience fatigue, which does not seem to be exclusively related to the degree of anemia but can also be caused directly by activation of the complement system [1,3,62]. The exact frequency has not been determined.

Venous thromboembolism — In a series of 72 individuals diagnosed with CAD from Denmark, an increased rate of venous thromboembolism (VTE) was observed as compared with age- and sex-matched controls [41]. The risk was not statistically significant and there were some methodology issues. A significant risk of VTE has been demonstrated, however, in subgroups with severe hemolysis [69].

A retrospective study involving a cohort of 608 individuals diagnosed with CAD from an insurance-based registry and nearly 6000 matched controls recorded thromboembolic events during a 10-year period (venous and arterial) in 30 percent of those with CAD versus 18 percent of controls (adjusted hazard ratio [HR], 3.1; 95% CI 2.24-4.30) [70]. A possible risk of arterial thrombosis is more controversial.

We do not routinely administer prophylactic anticoagulation to reduce the risk, but anticoagulation should be considered in acute exacerbations and if additional risk factors are present [32].

DIAGNOSTIC EVALUATION

When to suspect CAD — Delays in diagnosis are common, with a delay of one or more years between symptom onset and diagnosis in many cases [32,33].

Any patient with autoimmune hemolytic anemia (AIHA) should have a sufficient diagnostic workup to establish the subtype, including the possibility of CAD. In particular, primary CAD or secondary cold agglutinin syndrome (CAS) may be suspected in an individual with cold-induced symptoms (eg, pain and discomfort in the extremities with exposure to cold or on swallowing cold liquids or foods). CAD or CAS may also be suspected in a person with unexplained hemolytic anemia or red blood cell (RBC) agglutination in a cooled blood collection tube or on the peripheral blood smear. A clue to the latter may be a very high mean corpuscular volume (MCV), a spurious result caused by RBC agglutination.

The suspicion for secondary CAS is increased in the setting of an infectious disease, autoimmune syndrome, or lymphoproliferative disorder. (See 'Associated disorders' above.)

CBC, blood smear, and hemolysis testing — The typical diagnostic approach in any suspected hemolytic anemia generally starts with a complete blood count (CBC) and review of the red blood cell indices and/or the peripheral blood smear. This may be followed by testing for hemolysis including haptoglobin, lactate dehydrogenase (LDH), indirect bilirubin, and direct antiglobulin (Coombs) testing (DAT).

Findings consistent with CAD include the following:

CBC – Anemia (may be absent if hemolysis is mild and/or reticulocytosis is sufficient to compensate).

The mean corpuscular volume (MCV) may be low, normal, or high depending on the degree of reticulocytosis

Spurious macrocytosis can also occur if the sample is cooled during processing or when it passes through the automated analyzer [71,72]

The white blood cell (WBC) count and platelet count are typically normal, although there may be leukocytosis or leukopenia if there is an infection or bone marrow disorder

Blood smear – RBC agglutination (picture 1) may be apparent (occasionally this can be seen in the collection tube (picture 5)); spherocytes may be present but are usually not abundant.

Reticulocyte count – Usually, the reticulocyte count is increased if there is ongoing (chronic) hemolysis. The reticulocyte count may be normal if hemolysis has just occurred and there has been insufficient time for reticulocytes to appear in the peripheral blood; if there is an underlying bone marrow disorder that interferes with compensatory erythropoiesis; or if the autoantibody binds to RBC precursors as well as mature RBCs.

LDH, bilirubin, haptoglobin – When hemolysis is present, the LDH and bilirubin are increased and the haptoglobin is decreased or absent.

Coombs test – The direct Coombs test (DAT) is positive for the complement component C3d and generally negative for immunoglobulin; a polyspecific Coombs test will be positive. If an IgG antibody accompanies the cold agglutinin, the Coombs test may also be weakly positive for IgG; this has been reported in up to one-quarter of patients [11,33].

Importantly, a positive DAT in the absence of hemolysis is not sufficient to make the diagnosis of CAD [8].

Complement C3 and, in particular, C4 levels are often reduced, reflecting a continuous consumption [11]. However, serum complement levels generally are not helpful in the evaluation for CAD, as they are relatively nonspecific and may depend on the patient's clinical status.

Antibody titer and thermal amplitude — Cold agglutinin titer should be measured in all patients with suspected CAD; thermal amplitude is generally restricted to complex management cases.

Titer – The cold agglutinin titer reflects the strength (concentration and avidity) of the antibody. Titer is determined by testing serial dilutions of patient serum for their ability to agglutinate RBCs. The titer is the highest dilution at which cold-induced agglutination of RBCs occurs.

Typical cold agglutinin titers in CAD are quite high. The accepted threshold for diagnosis is 64, and most experts consider a titer above 512 to be clinically significant; in many cases the titer is greater than 2048 [33]. Titers lower than this are very unlikely to be clinically significant; up to 95 percent of healthy blood donors in one study had cold agglutinin titers ≤4 [73].

Thermal properties – The cold agglutinin thermal range reflects the temperature range over which the antibody will bind to the RBC antigen. The thermal amplitude (TA) is the highest temperature at which the antibody will bind the antigen. Most clinically significant cold agglutinins have a thermal amplitude that exceeds 28° to 30°C [34].

TA is more important for clinical manifestations than titer but more difficult to measure in the laboratory [8]. Thus, we typically obtain TA testing once at the initial assessment to determine its clinical importance, but we do not use it to guide therapy. TA testing is especially important for complex cases in which initial testing is indeterminate or for surgical planning for individuals undergoing procedures with planned cardioplegia, so that the patient's body temperature can be maintained above the TA. The most important reading for the TA is the presence of agglutination at body temperature.

Importantly, care must be taken in collecting blood for cold agglutinin analysis; the specimen must be maintained at 37 to 40°C until the clot has formed and retracted and the serum has been removed; otherwise, the cold agglutinin may precipitate and be inadvertently removed from the sample during serum preparation.

Diagnosis — Generally accepted diagnostic criteria include the following [8,74,75]:

Evidence of hemolysis (eg, high reticulocyte count, high LDH, high indirect bilirubin, low haptoglobin)

Positive direct antiglobulin (Coombs) test for C3d only (or, in a minority, C3d plus weak IgG)

Cold agglutinin titer of ≥64 at 4°C

Caveats about sample handling are noted above. (See 'Antibody titer and thermal amplitude' above.)

Testing for underlying disorders — Evaluation for an underlying disorder that could be responsible for cold agglutinins is appropriate in most individuals, especially older adults and those who have evidence of an infectious, autoimmune, or lymphoproliferative disorder [8]. (See 'Associated disorders' above.)

In some cases, a thorough history and physical examination is sufficient. Additional studies (laboratory testing and/or radiologic imaging) such as the following are often indicated:

Infection – Testing for an infectious disorder is appropriate in those with fever and/or respiratory symptoms, particularly if the duration of symptoms is short. Testing for infectious mononucleosis is especially relevant in a child or young adult. Testing for mycoplasma is especially relevant in an individual with atypical pneumonia. (See "Infectious mononucleosis" and "Mycoplasma pneumoniae infection in children", section on 'Diagnosis' and "Mycoplasma pneumoniae infection in adults".)

Autoimmune disorder – Testing for an autoimmune disorder is reasonable in those with arthralgias or arthritis, malar rash, or cytopenias. This may include serologies for systemic lupus erythematosus (SLE) or others depending on the clinical presentation. (See 'Infections and autoimmune disorders' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

Lymphoproliferative disorder or lymphoid malignancy – Testing for a lymphoproliferative disorder or lymphoid malignancy (eg, non-Hodgkin lymphoma or Waldenström macroglobulinemia) is done if there is weight loss, lymphadenopathy, hepatosplenomegaly, lymphocytosis, and/or cytopenias; in an older individual without evidence of infection or autoimmune disease; or in any patient with chronic hemolysis from a cold agglutinin. Details of testing are presented separately. (See "Laboratory methods for analyzing monoclonal proteins" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

Most individuals who have chronic primary CAD likely have a very indolent lymphoproliferative disorder in the bone marrow, especially those with a kappa-restricted IgM cold agglutinin with a high titer. Details of the immunophenotype and genetic changes are discussed above. (See 'Cold agglutinins' above and 'Primary CAD-associated lymphoproliferative disorder' above.)

The results of this evaluation have important implications for therapy, as follows:

Most cold agglutinins that are associated with infections or autoimmune disorders are likely to be polyclonal and to resolve spontaneously with resolution of the infection (which may include antibiotic therapy) or treatment of the autoimmune disorder. These patients can be advised to avoid cold temperatures until they recover. (See 'Cold avoidance' below.)

In severe cases with significant hemolytic anemia, patients must be kept under close observation until the hemolysis has resolved. It is possible that treatments directed at the reticuloendothelial clearance of the cold agglutinins (eg, glucocorticoids, splenectomy) may be somewhat effective, especially if there is mixed warm and cold autoimmune hemolytic anemia (AIHA).

Cold agglutinins associated with lymphoid malignancies or chronic CAD associated with a lymphoproliferative disorder in the bone marrow are very likely to be monoclonal and will not resolve spontaneously or respond to glucocorticoids or splenectomy. If these individuals have significant hemolysis, treatment will require a therapy to eradicate the clone of cells producing the cold agglutinin. (See 'Therapies directed at the pathogenic process' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CAD and secondary cold agglutinin syndrome (CAS) includes other causes of cold-induced symptoms and other hemolytic anemias. The table summarizes differences among the antibody-mediated conditions that are activated by cold temperature (table 1).

Cold-induced symptoms – Other causes of cold-induced symptoms include primary Raynaud phenomenon, Raynaud phenomenon associated with other underlying disorders, and cryoglobulinemia.

Primary and other secondary Raynaud phenomenon – Raynaud phenomenon can be caused by a number of conditions including CAD and secondary CAS. Unlike patients with CAD or secondary CAS, individuals with these other disorders have no evidence of a cold agglutinin on the blood smear or laboratory testing, and in many cases, these individuals do not have autoimmune hemolytic anemia (ie, they have a negative Coombs test). Evaluation of Raynaud phenomenon is discussed separately. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Cryoglobulinemia – Cryoglobulins are immune complexes that form in cold temperatures and can cause a number of findings including arthralgias, purpura, skin ulcers, glomerulonephritis, or peripheral neuropathy. Like CAD or secondary CAS, individuals with certain types of cryoglobulinemia (especially type I and mixed cryoglobulinemias) can have cold-induced Raynaud phenomenon, and they may have a history of an infection (often, hepatitis C virus [HCV]), a monoclonal gammopathy, or an autoimmune disorder. Unlike patients with CAD or secondary CAS, individuals with cryoglobulinemia have no evidence of a cold agglutinin on laboratory testing, and in many cases these individuals do not have autoimmune hemolytic anemia (AIHA; ie, they have a negative Coombs test). (See "Overview of cryoglobulins and cryoglobulinemia" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Hemolytic anemia – Other causes of hemolytic anemia include warm AIHA, drug-induced hemolytic anemia, hemolytic transfusion reactions (HTRs), and paroxysmal cold hemoglobinuria (PCH). Differences in the findings of direct antiglobulin testing (DAT; Coombs testing) in these conditions are summarized in the table (table 3).

Warm AIHA and drug-induced hemolytic anemia – Warm AIHA is the most common type of immune hemolytic anemia. Like CAD or secondary CAS, in warm AIHA and some forms of drug-induced hemolysis, there is usually evidence of extravascular immune hemolysis (eg, high lactate dehydrogenase [LDH] and indirect bilirubin, low haptoglobin, increased reticulocyte count, positive Coombs test). Unlike CAD or secondary CAS, in warm AIHA and drug-induced hemolytic anemia, there are usually no cold-induced symptoms, the Coombs test is positive for IgG rather than complement, and the blood smear shows spherocytes but no red blood cell (RBC) agglutination (table 3). (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Drug-induced hemolytic anemia".)

Paroxysmal cold hemoglobinuria – PCH is a cold-induced autoimmune hemolytic anemia associated with an IgG antibody, usually with anti-P specificity; a positive Donath-Landsteiner test; and, frequently, a recent history of a viral infection. The Coombs test may be positive for bound complement, but the cold agglutinin titer is, at most, only moderately elevated (ie, <160). (See "Paroxysmal cold hemoglobinuria".)

Hemolytic transfusion reactions – HTRs can be acute or delayed. Both types of HTRs are caused by alloantibodies that react with antigens on the transfused RBCs. Like CAD and secondary CAS, HTRs can show findings of immune hemolysis. Unlike CAD and secondary CAS, HTRs do not have cold-induced symptoms or red cell agglutination, and laboratory evaluation of an HTR will reveal the relevant red blood cell antigen in the transfused unit. (See "Hemolytic transfusion reactions".)

MANAGEMENT

Overview of the approach to treatment — Not all individuals with cold agglutinins have clinical manifestations. For those who do, treatment is directed at minimizing cold-induced symptoms, maintaining an acceptable hemoglobin level, and, if required, addressing underlying disorders [8,76].

Major treatment decisions are summarized in the flowchart (algorithm 1).

In a retrospective series of 232 individuals, 175 (76 percent) had received CAD-directed medical therapy, whereas the remaining 24 percent were treated with supportive/symptomatic care alone [32].

Cold-induced symptoms – The main therapy is avoidance of cold temperatures (see 'Cold avoidance' below). For those with chronic or severe symptoms and a monoclonal cold agglutinin, therapy directed at the underlying clone is usually appropriate. (See 'Therapies directed at the pathogenic process' below.)

Anemia – Compensated hemolysis or hemolysis with mild, stable anemia may not require specific treatment. For individuals with severe or symptomatic anemia, transfusions can be given, and plasmapheresis may be used as a temporizing measure. Therapy to reduce antibody production is indicated in these individuals. (See 'Emergency and supportive therapies for anemia' below and 'Therapies directed at the pathogenic process' below and 'Anti-complement therapies' below.)

Underlying disorders – Management is individualized according to the specific disorder and patient's clinical status. If no underlying disorder is found in an individual with chronic CAD, the disorder is presumed to be due to a low-grade lymphoproliferative disorder (ie, a very indolent clone that may or may not progress to a lymphoid malignancy), and antibody production is usually targeted with a rituximab-containing regimen. (See 'Associated disorders' above and 'Therapies directed at the pathogenic process' below.)

Patients with CAD requiring therapy should be considered for inclusion in prospective trials if available.

Cold avoidance — Cold avoidance is used to reduce cold-induced symptoms and hemolysis.

Ambulatory patients — Avoidance of cold demands constant vigilance to avoid cold rooms or environments, cold water (eg, in public sinks), and cold liquids that may be served in public restaurants. Space heaters may be necessary to keep room temperature at adequate levels.

Outdoors (or in cold indoor spaces), warm clothing should protect acral areas; this includes warm shoes, stockings, gloves, and scarves or earmuffs that protect the extremities, nose, and ears. It may be useful to avoid cold foods or liquids if these cause symptoms.

Some individuals who live in cold parts of the world may be able to spend colder months in a more temperate region. Accommodations should be made for those with jobs that include cold exposure.

Hospitalized patients — Avoidance of cold is especially important during hospitalization and surgery, when the affected individual may have less control over their ambient temperature and the temperature of intravenous solutions [8].

Intravenous solutions and blood products should be warmed to an appropriate temperature before infusion. For blood transfusions, the temperature must be warm but cannot be above 40°C. (See 'Transfusions' below.)

Space heaters and blanket should be provided as needed, and liquids without ice should be available for drinking.

Fever should be treated with antipyretics and prompt treatment of infections rather than with cooling blankets [77].

If any hypothermic surgical procedures are required, advance multidisciplinary planning should include input from the consulting hematologist, laboratory medicine service, anesthesiologist, and surgeon regarding precautions to prevent acute hemolytic crisis in the operating room. This may include preoperative testing to characterize the thermal amplitude of the cold agglutinin, plasmapheresis, and/or warm cardioplegia [78-81]. Prophylactic use of eculizumab in this situation has been described in a case report [82]. (See 'Antibody titer and thermal amplitude' above and 'Plasmapheresis or IVIG as a temporizing measure' below.)

Emergency and supportive therapies for anemia

Plasmapheresis or IVIG as a temporizing measure — For critical hemolysis when the delay of several weeks to days before immunosuppressive therapy takes effect is unacceptable, plasmapheresis or intravenous immune globulin (IVIG) may be used (algorithm 1).

Plasmapheresis – Plasmapheresis is thought to be highly effective in removing cold agglutinins because these are almost always IgM antibodies that are distributed almost entirely intravascularly. (See 'Cold agglutinins' above.)

There have been no large trials or series to assess the efficacy of plasmapheresis in CAD, but case reports have described reduction of hemolysis and in one case, improvement in severe acrocyanosis [10,83]. Therapeutic apheresis for severe CAD is considered a category II indication by the American Society for Apheresis. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

While plasmapheresis can remove IgM, it does nothing to decrease IgM production and thus must be seen as a temporizing measure to be used only until other therapies become effective. The optimal exchange volume and number of exchange procedures remain unproven; 1 to 1.5 times the plasma volume per exchange seems reasonable [2,75]. Albumin should be used as the exchange fluid instead of plasma, both to avoid exacerbating the disease by providing additional complement as well as to reduce plasma-related adverse effects [68,75]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

The procedure should be performed in a warm environment and precautions taken to prevent cooling, which could exacerbate cold symptoms and hemolysis [84]. Since apheresis does not address the source of antibody production, it is essential that therapy to address the underlying cause is initiated as soon as possible (see 'Therapies directed at the pathogenic process' below). If performed to prepare a patient for surgery, it should be performed no more than one to two days before the procedure, so that the antibody does not re-accumulate [83]. After removal, the half-life for re-accumulation of the IgM is approximately five days.

Cryofiltration apheresis (CFA) is a form of plasmapheresis that allows removal of the cold agglutinins without removal of other plasma proteins, and thus it does not require a replacement fluid such as donor plasma or albumin [85]. This is because the patient's plasma can be separated from red blood cells (RBCs), cooled within the circuit, the precipitated cryoproteins removed using a filter, and the remaining plasma warmed and returned to the patient. In a series of five patients with CAD treated with CFA, two had an excellent response after a single treatment (including one who subsequently underwent coronary artery bypass grafting); the remaining three tolerated the procedure well but their improvement was attributed to other interventions [85].

IVIG – There is less experience using IVIG in CAD, and the efficacy has not been well characterized.

Transfusions — Transfusions can and should be provided when indicated. Some individuals may have mild disease and may only require transfusions in the setting of severe hemolysis precipitated by infection or during the winter months [8,38].

Unlike with warm autoimmune hemolytic anemia (AIHA), pretransfusion testing and crossmatching can be performed without interference by the autoantibody, provided the transfusion service is alerted to the presence of the cold agglutinin and cooling of the patient sample is avoided [86].

The blood (and any co-administered solutions) should be warmed appropriately prior to transfusion (typically, using a blood warmer to raise the temperature to body temperature) [8,75]. It is important not to heat the blood above 40°C because this will cause thermal hemolysis. (See "Hemolytic transfusion reactions", section on 'Non-immune hemolysis'.)

●The patient should be kept warm, especially in the extremity through which the transfusion is administered.

Erythropoietin — Patients with severe anemia and an inadequate bone marrow response (low reticulocyte count) may benefit from modest doses of erythropoietin (40,000 units subcutaneously once or twice a week), although evidence to support this approach in CAD is based on small retrospective studies [87,88].

Therapies directed at the pathogenic process

Indications for anti-B-cell therapy (primary CAD)

In typical primary CAD, with or without a detectable low-grade bone marrow lymphoproliferative disorder, treatment is indicated for individuals who have symptomatic anemia or cold-induced ischemic symptoms interfering with daily living (algorithm 1). Asymptomatic individuals can be followed without drug therapy.

Treatment aims at targeting the pathogenic B-cell clone in the bone marrow to reduce the production of monoclonal cold agglutinin. Therapy generally involves rituximab in combination or as monotherapy.

For most individuals who require treatment (due to significant hemolytic anemia or cold-induced symptoms), we generally use a rituximab-containing regimen such as rituximab plus bendamustine. (See 'Rituximab-containing regimens' below.)

For individuals for whom a rituximab-containing regimen is ineffective, we use bortezomib. (See 'Bortezomib' below.)

Ibrutinib can also be considered as a second-line B-cell targeting therapy, although the effect has only been documented in retrospective studies [32,89].

For those with cold agglutinin syndrome (CAS) secondary to an overt lymphoma that requires treatment by itself, such as an aggressive B-cell lymphoma, there is no documented therapy apart from appropriate treatment for the specific type of lymphoma. Choice of regimen is discussed in separate topic reviews. (See "Initial treatment of limited stage diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Overview of the treatment of chronic lymphocytic leukemia" and "Treatment and prognosis of Waldenström macroglobulinemia".)

Patients with CAS secondary to infection have a polyclonal cold agglutinin that will resolve spontaneously, typically over two to four weeks following resolution of the infection. Antibiotics or antiviral therapies should be used when indicated, as discussed in separate topic reviews. (See "Mycoplasma pneumoniae infection in adults" and "Infectious mononucleosis".)

If an underlying autoimmune disorder is identified, treatment should be directed at the underlying disorder.

As noted above, glucocorticoids and splenectomy are not effective therapies in the majority of patients with CAD, in contrast to warm AIHA where these therapies are generally very effective [3,8,11,33]. Glucocorticoids may downregulate phagocytosis, but they do not block antibody production. Exceptions may include individuals with IgG cold-reacting antibodies, antibodies with a higher thermal amplitude that cause some warm hemolysis, or mixed warm and cold AIHA. Splenectomy is likely to be ineffective because the liver, not the spleen, is the main site of RBC phagocytosis in CAD. As with glucocorticoids, splenectomy may be effective in rare individuals who have a high thermal amplitude antibody or a mixed warm and cold AIHA [9,11].

Other cytotoxic or immunosuppressive therapies that have been tried include cyclophosphamide or chlorambucil (often in combination with glucocorticoids) or interferon alfa [33,90-92]. These might be appropriate in selected patients if rituximab and/or bortezomib have failed to reduce antibody production. Individuals treated with these therapies should be aware of the limited evidence for efficacy.

Rituximab-containing regimens — Rituximab may be used alone or in combination with other agents. We generally individualize decisions about adding a second agent, balancing the toxicity profile and other burdens with the severity of disease.

Rituximab plus bendamustine produces high response rates and often complete responses lasting for many years. However, toxicities may be greater than with rituximab monotherapy, limiting use of this combination in frail individuals [8,32].

Rituximab plus fludarabine is more toxic and should be reserved for third-line therapy in selected patients.

Rituximab plus bendamustine — We generally prefer rituximab plus bendamustine for individuals with chronic primary CAD, based on high, durable response rates demonstrated in observational studies [3]. (See 'Evidence for efficacy' below.)

Rituximab can be given at a dose of 375 mg/m2 on day 1, with bendamustine given at a dose of 90 mg/m2 on days 1 and 2 for four cycles at a 28-day interval. As noted below, we generally give four cycles of therapy. (See 'Monitoring and duration of therapy' below.)

It is useful to note that bendamustine plus rituximab is a highly effective combination for Waldenström macroglobulinemia (WM), which is one of the lymphoid malignancies most often associated with CAD. This combination was effective in treating CAD in two older patients with WM after multiple courses of other agents were ineffective [93,94]. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Bendamustine plus rituximab'.)

Rituximab single agent or rituximab plus interferon — Monotherapy with rituximab is a good option for individuals who cannot tolerate multi-agent regimens.

Typical rituximab doses when used as a single agent are based on those used to treat B-cell malignancies (eg, 375 mg/m2 weekly for four weeks) [95,96]. Rituximab can be given at a dose of 375 mg/m2 once weekly for four weeks, with or without interferon alfa at a dose of 5 million units subcutaneously three times per week, starting two weeks before retreatment with rituximab.

In a series of 27 patients with CAD treated with this regimen, responses were seen in 54 percent [95]. The median duration of response was 11 months. There were no serious adverse effects.

Lower doses of rituximab (eg, 100 mg fixed dose weekly for four weeks) have also been used, but with more frequent failures in CAD than in warm AIHA [97].

Rituximab plus fludarabine – Rituximab can be given at a dose of 375 mg/m2 on days 1, 29, 57, and 85, with oral fludarabine 40 mg/m2 on days 1 through 5, 29 through 34, 57 through 61, and 85 through 89.

In a prospective study involving 29 patients treated with this regimen (10 of whom were previously treated with single-agent rituximab without a response), responses were seen in 76 percent, with complete responses in 21 percent [98]. The estimated median response duration was in excess of 66 months. Grade 4 hematologic toxicity (absolute neutrophil count <500/microL) occurred in four patients (14 percent), and fludarabine was discontinued or dose-reduced in 13 (45 percent).

Monitoring and duration of therapy — Therapy is monitored by following the hemoglobin level, markers of hemolysis (eg, bilirubin, haptoglobin, lactate dehydrogenase [LDH], reticulocyte count), and IgM level. The frequency of testing is individualized depending on the severity of hemolytic anemia.

Responses to rituximab-based combinations can be delayed by several months and can deepen with time. Therefore, we do not continue these therapies beyond four cycles; conversely, we do not stop therapy in patients who have not had a response after three or fewer cycles [32].

Evidence for efficacy — The efficacy of rituximab appears to be reasonable in CAD, although slightly less than in warm AIHA [99]. Randomized trials have not been performed. Case series have reported response rates of more than 50 percent; almost all responses are partial. As examples:

Evidence for rituximab-containing regimens

In a 2013 retrospective series of 89 patients with CAD treated with a variety of therapies, rituximab-based therapy gave response rates of 83 percent (single agent) and 79 percent (combination therapy) [33]. These rates were higher than many of the other immunosuppressive or cytotoxic agents.

In a 2006 series of 86 patients with CAD treated with a variety of therapies, rituximab was used in 52, with response rates on the order of 67 percent; complete response was more likely with combination therapy than with single-agent rituximab, and rituximab-based therapy was more effective than other immunosuppressive or cytotoxic agents [11].

Smaller series have reported similar response rates with rituximab, alone or in combination with other therapies [95,96,98-101].

Evidence for rituximab plus bendamustine – Observational data show good outcomes with rituximab plus bendamustine and suggest that rituximab plus bendamustine may be less toxic and associated with a higher rate and longer duration of response than rituximab plus fludarabine.

In a prospective study involving 45 patients treated with this regimen, responses were seen in 32 individuals (71 percent), with complete responses in 18 (40 percent). Of those who had a response, only three (<10 percent) relapsed after 32 months [101]. Grade 3 neutropenia was seen in 15 patients (33 percent), and infection developed in five (11 percent). The median time to response was 1.9 months (upper range, 12 months), with even longer time to optimal response in some patients.

A follow-up study that included additional individuals showed long-lasting responses [32]. Of 104 patients who received at least one course of rituximab plus bendamustine or rituximab plus fludarabine, rituximab plus bendamustine was associated with the following favorable outcomes:

-Higher overall response rate – 78 versus 62 percent

-Higher complete response rate – 53 versus 38 percent

-Higher response rate at five years – 77 versus 71 percent

The median response duration with rituximab plus bendamustine was >88 months. There was a trend towards a higher rate of late-occurring malignancies in patients who received rituximab plus fludarabine (31 percent, versus 9 percent with rituximab plus bendamustine; not statistically significant).

Bortezomib — Bortezomib is a proteasome inhibitor used in lymphoid (B-cell) malignancies. We would use bortezomib (short course, as described in the study below) in individuals with an underlying B-cell or plasma cell disorder such as monoclonal gammopathy if rituximab-containing regimens are ineffective or contraindicated [8].

Evidence for the efficacy of bortezomib comes from a 2018 study involving 21 individuals with CAD who had anemia and chronic hemolysis (hemoglobin <10 g/dL) and for whom at least one prior therapy had been ineffective [102]. They were treated with bortezomib as a "short course" (1.3 mg/m2 given intravenously on days 1, 4, 8, and 11). Oral acyclovir was administered as prophylaxis for herpes zoster reactivation. Six of 19 evaluable patients (32 percent) had a response (defined as transfusion independence or a 2 g/dL increase in hemoglobin level); the response was complete in three and partial in three. In four of the six individuals, the response was lasting (median duration, 16 months). Therapy was well tolerated with only a single grade 3 to 4 adverse event that was considered treatment-related (upper respiratory tract infection). Case reports and our experience are consistent with these results [103,104].

Daratumumab — Two case reports have described promising results with daratumumab in individuals with severe CAD refractory to B-cell directed therapies [105,106]. Further data are needed before this approach is adopted.

Anti-complement therapies — Therapies that target the classical complement pathway components responsible for extravascular hemolysis in CAD can be used to reduce transfusion requirements and improve anemia and fatigue [62].

Complement-directed therapies do not eliminate the cells producing the cold agglutinins, and they would not be expected to improve cold-induced symptoms related to RBC agglutination, as agglutination is mediated by the IgM molecules and is complement independent [8]. Inherited deficiencies of proximal complement components cause systemic lupus erythematosus (SLE) and recurrent bacterial infections, suggesting that these proteins have important roles in normal immune function. However, appearance of antinuclear antibodies or occurrence of clinical SLE has not been reported in clinical studies of proximal complement inhibition [62,107]. (See "Inherited disorders of the complement system", section on 'C1 deficiency'.)

Furthermore, complement-directed therapies will have to be continued indefinitely, in contrast to B cell-directed therapies, which are temporary. Therefore, complement-directed therapies are generally reserved for individuals whose disease does not improve with immunosuppressive therapies such as rituximab, bortezomib, and/or fludarabine, those who cannot take these therapies, or those who require a more rapidly acting or transient blockade of hemolysis. (See 'Therapies directed at the pathogenic process' above.)

Eculizumab and related monoclonal antibodies that target the more distal complement component C5 are not expected to lessen hemolysis, which is mostly extravascular and mediated by upstream components of the classical complement pathway, although reports have described reduction of hemolysis in selected individuals [69,108-111]. (See 'Mechanism of hemolysis' above.)

Sutimlimab (anti-C1) — Complement component C1 is an attractive target because it has enzymatic activity and is upstream of a number of other classical pathway components (figure 1). C1 consists of three subunits (C1r, C1s, and C1q) (figure 2). (See "Complement pathways".)

Sutimlimab (previously called TNT009 or BIVV009) is a humanized monoclonal antibody targeting C1s that can reduce extravascular hemolysis mediated by C3b [35,112-115]. It was approved for CAD in early 2022 [116].

Indications – The exact indications for sutimlimab in CAD have not been determined. Based on available evidence, we suggest sutimlimab for the following individuals:

Patients with symptomatic anemia who are awaiting the effects of definitive therapy (with a rituximab-containing regimen or treatment directed at a cause of secondary CAS) or those in whom a rituximab-containing regimen is not appropriate or contraindicated. During the COVID-19 pandemic, this group will include individuals who are not fully vaccinated or who face a high risk of severe disease if infected and as a result wish to avoid rituximab, which is immunosuppressive.

Patients with hemolytic anemia that is unresponsive to B cell-directed therapies.

Patients who require a rapid response due to severe anemia or acute exacerbations of hemolysis that do not resolve spontaneously. In these cases, sutimlimab may be used as a "bridge" to B cell-directed approaches because it has a much more rapid onset of response. Severe anemia can be controlled with sutimlimab while B cell-directed therapy is initiated and while waiting for cold agglutinin production to cease.

Individuals who are undergoing cardiac surgery. In these individuals, a prophylactic dose of sutimlimab given preoperatively may prevent a CAD exacerbation associated with hypothermia [1,3,62,82,117,118]. (See "Management of special populations during cardiac surgery with cardiopulmonary bypass", section on 'Cold agglutinin disease'.)

Sutimlimab is generally not appropriate as standalone therapy if bothersome, cold-induced circulatory symptoms are part of the indication for treatment [1,62]. Cold-induced symptoms are caused by RBC agglutination and are unlikely to be reduced by complement blockade.

Dosing – The dose is given intravenously, once weekly for two weeks and once every two weeks thereafter:

Weight 39 to 75 kg – 6500 mg

Weight ≥75 kg – 7500 mg

Patients should receive vaccinations against encapsulated bacteria (Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) at least two weeks before starting sutimlimab; if therapy is started urgently, vaccines should be provided as soon as possible.

The duration of therapy depends on whether cold agglutinins continue to be produced, since sutimlimab only blocks hemolysis and does not treat the source of cold agglutinin production. For individuals in whom the production of cold agglutinins resolves (because infection resolves or definitive therapy has been used to treat an underlying cause), it may be possible to discontinue sutimlimab; further evidence is awaited. For those with ongoing cold agglutinin production (eg, an individual with a lymphoproliferative disorder who is avoiding rituximab during the COVID-19 pandemic), it is continued.

Adverse effectsSutimlimab can increase the risk of serious bacterial infections, especially from encapsulated organisms. Based on its mechanism of action, sutimlimab might increase the risk of autoimmune diseases such as systemic lupus erythematosus (SLE), although this has not been observed in clinical studies. Hemolysis will usually recur after discontinuation of therapy, unless the underlying condition causing cold agglutinin production has been treated.

Supporting evidence – A 2022 trial (CADENZA) that randomly assigned 42 patients with CAD and hemoglobin <10 g/dL to sutimlimab or placebo demonstrated increased mean hemoglobin and decreased fatigue stores [119]. The composite endpoint of increased hemoglobin and avoidance of transfusions and CAD medications was met in 73 percent in the sutimlimab arm and three percent in the placebo arm. Markers of hemolysis were significantly improved, with normalized bilirubin in all the patients in the sutimlimab arm This trial and other studies excluded patients with >10 percent lymphoid infiltration in the bone marrow; therefore, the favorable effect of sutimlimab is not documented in this subgroup.

Prior single arm studies also documented increases in hemoglobin in individuals treated with sutimlimab [62,107,120]. A prospective study of longer duration of use (washout period and retreatment for a total of 52 months) demonstrated sustained responses, with stable hemoglobin and reduced hemolysis markers [121]. All of the studies of sutimlimab have shown that therapy was well tolerated.

Inhibitors of C1q are also under investigation for reducing hemolysis in CAD [122].

Pegcetacoplan (anti-C3) — Complement protein C3 is the point of convergence between all three complement-activating pathways and the initiation of the terminal (lytic) pathway (figure 1). C3 inhibition is expected to block the entire complement system, including the classical pathway and ensuing C3b opsonization, which are the main drivers of hemolysis in CAD, and the terminal pathway, which is of importance in some patients and some situations [123].

Pegcetacoplan (previously termed APL-2) is a pegylated cyclic peptide inhibitor of C3 that is designed for subcutaneous administration. Preliminary outcomes from a study of pegcetacoplan therapy in AIHA, reported in abstract form, documented an efficacy in two individuals with CAD, who had an increase in hemoglobin levels by 3 g/dL and 5.7 g/dL, respectively, after 8 to 12 weeks of treatment [123,124]. Both individuals had an increase in hemoglobin to >13 g/dL, and the drug was well tolerated. Participants were vaccinated as in the sutimlimab trials. Possible concerns and limitations are expected to be similar to sutimlimab. Further trials will need to evaluate the risk of infection with encapsulated bacteria.

PROGNOSIS — Median survival appears to be similar to or only slightly decreased compared with an age-matched population [11,32,33]. In the largest series, survival from the time of diagnosis (at a median age of 68 years) was 16 years, with an estimated five-year survival of 83 percent [32].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Autoimmune hemolytic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathophysiology – Cold agglutinins are immunoglobulin M (IgM) antibodies against red blood cells (RBCs), active at temperatures below normal body temperature. They can cause RBC agglutination and extravascular hemolysis with anemia. (See 'Terminology and distinction among syndromes' above and 'Pathogenesis' above and 'Associated disorders' above.)

Primary cold agglutinin disease (CAD) has characteristic immunophenotypic and genetic changes (picture 2).

Secondary cold agglutinin syndrome (CAS) occurs with certain infections (Mycoplasma pneumoniae, infectious mononucleosis), autoimmune disorders, and lymphoid malignancies.

Prevalence – The prevalence is 5 to 20 per million; CAD constitutes approximately one-fifth of autoimmune hemolytic anemias (AIHAs). Many individuals with primary CAD are >60 years. (See 'Epidemiology' above.)

Clinical features – CAD can cause cold-induced acrocyanosis, livedo reticularis, Raynaud phenomenon, and AIHA (mild to severe). (See 'Clinical manifestations' above.)

Evaluation – The CBC and RBC indices may show anemia and spurious macrocytosis due to RBC agglutination (picture 1). Hemolysis is Coombs-positive for complement. The cold agglutinin titer is the highest dilution at which cold-induced RBC agglutination occurs; the specimen must be maintained at 37 to 40°C until the clot has formed and retracted and the serum has been removed. The table lists distinctions from paroxysmal cold hemoglobinuria (PCH) and cryoglobulinemia (table 1). (See 'Diagnostic evaluation' above and 'Terminology and distinction among syndromes' above.)

Diagnosis – CAD is diagnosed by AIHA, positive direct Coombs for complement C3d [usually negative for IgG]), and cold agglutinin titer ≥64 at 4°C. (See 'Diagnosis' above and 'Antibody titer and thermal amplitude' above.)

Post-diagnostic testing – Evaluation for an underlying disorder is appropriate, especially in older adults and individuals with suspected infectious, autoimmune, or lymphoproliferative disorders. Serum protein electrophoresis (SPEP) and immunoglobulin class quantification should be performed. If an underlying disorder is not identified, bone marrow with flow cytometry is obtained. Most individuals with primary CAD have an indolent lymphoproliferative disorder in the bone marrow. (See 'Testing for underlying disorders' above.)

Differential diagnosis – The differential diagnosis includes other causes of Raynaud phenomenon, warm AIHA, drug-induced hemolytic anemia, transfusion reactions, and PCH. (See 'Differential diagnosis' above.)

Management

All patients – Our approach is summarized in the flowchart (algorithm 1). All patients should avoid cold exposures until the underlying cause of CAD has resolved or been eliminated. This demands constant vigilance and is especially important in hospitalized patients and with cardiac surgery. In extreme cases, it may be possible to reduce the cold agglutinin using plasmapheresis (if emergency cardiac surgery with cold cardioplegia is required). (See 'Cold avoidance' above.)

Severely affected patients – For symptomatic individuals (anemia, fatigue, cold-induced symptoms), the need for intervention depends on severity. (See 'Overview of the approach to treatment' above.)

-For severe anemia (hemoglobin <7 to 8 g/dL or hemodynamic compromise), RBC transfusions should be provided. In extreme cases, plasmapheresis can be used to remove the cold agglutinin. (See 'Emergency and supportive therapies for anemia' above.)

-For anemia that requires transfusions or causes severe symptoms, we suggest sutimlimab (Grade 2C). Sutimlimab can be used as a temporizing measure until cold agglutinins resolve or are eliminated (as a bridge while awaiting definitive therapy or prior to cardiovascular surgery), or chronically in individuals who cannot receive therapies to eliminate cold agglutinins (eg, if they wish to avoid rituximab during the COVID-19 pandemic) or if these therapies are ineffective. Sutimlimab only treats hemolysis and fatigue; it is not expected to treat or prevent cold-induced circulatory symptoms. (See 'Sutimlimab (anti-C1)' above.)

Patients with primary CAD – For patients with primary CAD, inclusion in prospective trials is encouraged.

-For anemia and/or symptoms, we suggest treatment with bendamustine plus rituximab rather than other regimens or no B-cell directed treatment (Grade 2C). Single agent rituximab may be more appropriate in frail individuals. Bortezomib or ibrutinib are also options. These therapies may take weeks to months to be effective, and faster-acting interventions to treat severe anemia may be needed until cold agglutinin production can be stopped.

-Asymptomatic individuals can be followed without drug therapy. (See 'Therapies directed at the pathogenic process' above.)

Patients with secondary CAS – For CAS, therapy is directed at the underlying disorder.

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Wendell F Rosse, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The UpToDate editorial staff acknowledges Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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