Hematology

Cold agglutinin disease

Cold agglutinin disease

What every physician needs to know:

Cold agglutinin disease (CAD) is a rare (approximately 1:100,000) disorder in which a red cell autoantibody, primarily IgM (immunoglobulin M), fixes complement in vivo. Complement fixation preferentially occurs at temperatures below 37°C, hence the term CAD. This results in mostly extravascular hemolytic anemia, but intravascular hemolysis may occur with hemoglobinemia and hemoglobinuria.

Anemia is variable but tends to be mild. However, patients can exhibit significant acrocyanosis. CAD may be monoclonal and occur either alone (idiopathic) or in association with non-Hodgkin's lymphoma. CAD may be polyclonal and occur in association with an infection, typically mycoplasma pneumonia and Epstein-Barr virus infection.

Are you sure your patient has cold agglutinin disease? What should you expect to find?

The diagnosis of cold agglutinin disease requires the presence of hemolytic anemia, a cold agglutination titer greater than 1:64 at 4 degrees Celsius, and a polyspecific direct Coombs test or monospecific direct Coombs for C3d.

What are the blood bank findings?

  • Positive indirect Coombs test (antibody screen)

  • Panel reactivity shows a pan-agglutinin typically enhanced by proteases such as ficin

  • Discrepancy between the ABO blood group system, front type and back type

  • Difficulty obtaining cross-match compatible red cells with the need to pre-warm the donor cells before crossmatching

- The blood bank can identify anti-I (I is a polysaccharide region of the glycoprotein on the RBC [red blood cell] membrane), which if monoclonal, indicates idiopathic CAD or lymphoma. If polyclonal, then this indicates mycoplasma pneumonia. If anti-i (i is an additional polysaccharide region of the glycoprotein on the RBC membrane) is present, then this indicates Epstein-Barr virus infection.

Beware of other conditions that can mimic cold agglutinin disease:

  • Warm antibody mediated autoimmune hemolytic anemia

  • Cryoglobulinemia

  • Paroxysmal cold hemoglobinuria

  • Drug induced hemolytic anemia

  • Raynaud's phenomenon

  • Systemic vasculitis with hemolysis

Which individuals are most at risk for developing cold agglutinin disease:

CAD is one and a half times more common in women than men. Also, patients with mycoplasma pneumonia and infectious mononucleosis have been shown to be at risk for CAD.

Lastly, CAD is typically found in older patients, as evident by two large retrospective studies, where the average age was over 60.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

These laboratory tests determine the presence of hemolytic anemia, agglutination, and cold agglutinin titers. The thermal amplitude (the upper temperature threshold where agglutination occurs) may be relevant if the patient is exposed to hypothermic conditions, such as may occur in cardiac surgery, but is not required for diagnostic purposes. (Table I)

Table I

Studies required and interpretations in CAD
Test Interpretation in CAD
Complete blood count with peripheral smear review Agglutination present
Indirect bilirubin Increased
LDH (lactate dehydrogenase) Increased
DAT (direct anti-globulin test) for anti-C3d (antibody to complement protein C3d) Present
Haptoglobin Decreased
Cold agglutinin titers Present
C3, C4, CH50 Decreased

What imaging studies (if any) will be helpful in making or excluding the diagnosis of cold agglutinin disease?

A chest x-ray should be performed in patients who present with respiratory complaints, since cold agglutinin disease can be secondary to mycoplasma pneumonia. An abdominal ultrasound should also be performed to assess for hepatosplenomegaly.

If you decide the patient has cold agglutinin disease, what therapies should you initiate immediately?

The initial treatment recommendation is to avoid cold exposure. If CAD is secondary to an infection or a lymphoproliferative disorder, treat the underlying cause. In cases with severe anemia, transfusion support may be necessary (see "blood bank findings" above).

More definitive therapies?

There is little response to steroids in CAD and no response to splenectomy. Treatment depends on whether the patient has a post-infectious form of the disease that may be self limited, or has true CAD.

Recently, encouraging results have been seen with the use of rituximab as either monotherapy or in combination with other agents such as fludarabine.

Overall response rates, defined as achieving at least transfusion independence, for monotherapy and combination therapy are 54% and 76% respectively.

Apheresis may also occasionally be helpful, as IgM is a predominantly intravascular protein.

What other therapies are helpful for reducing complications?

Treatment of underlying infections is important, not just in the management of post-infectious cold agglutin disease but also in CAD.

There is a known increase in hemolysis in 75% of patients with CAD during an infectious episode, presumably due to an increase in complement levels during the acute phase reaction. Avoidance of the cold as a preventative measure should be encouraged for all patients but has not shown proven efficacy.

What should you tell the patient and the family about prognosis?

The overall prognosis of idiopathic CAD is good with a median survival of 12.5 years from onset of clinical disease. Treatment responses have recently improved secondary to the use of rituximab. Monotherapy with rituximab has shown a mean duration of response of 11 months. Combination therapy with rituximab/fludarabine has a median duration of response of over 66 months, albeit with significant hematological toxicities.

Patients with CAD due to an underlying indolent lymphoproliferative disorder have a rare but possible chance to progress to diffuse large B cell lymphoma (on the order of 3 to 4% overall).

"What if" scenarios.

What if no IgM is detected?

IgG and IgA (immunoglobulin A and G ) are rarely associated with cold agglutinin disease but occasions have been documented. Additional cases have reported a lack of IgM (immunoglobulin M) detection through protein electrophoresis, but have found it via immunofixation. Alternatively a kappa:lambda ratio can be checked since over 90% of the cases of CAD showed a kappa:lambda ratio greater than 1:3.5.

A patient with CAD suddenly develops a worsening of their hemolytic anemia in the setting of a pneumonia. What should be done first?

Treatment of the infection with antibiotics if needed should be initiated immediately. Further treatment of the anemia with transfusions can be pursued depending on the degree of anemia. There would be no immediate role however for rituximab since this represents a CAD flare in the setting of infection.

Pathophysiology

IgM antibody (Ab) is produced either via a polyclonal response to infection, or as a monoclonal antibody associated with an underlying lymphoproliferative disorder. The IgM antibody is directed against either branched or unbranched carbohydrate antigens on the red cell surface. In cases of CAD, the IgM Ab is most frequently from kappa light chains, is specific for anti-I, and is encoded by the VH 4-34 segment of the rearranged heavy chain gene.

Due to its size, IgM can bind multiple antigen (Ag) sites on red blood cells, thereby causing agglutination. IgM binding occurs in the peripheral portions of the body where the temperature is lower. The Ab-Ag complex then leads to C3b binding to the red cell surface. As the red cell returns to the central circulation, the temperature increases and the IgM Ab detaches. C3b, however, remains bound and leads to red blood cell (RBC) destruction by the reticuloendothelial system especially in the liver. RBCs that are not destroyed see their C3b further cleaved into C3c and C3d. This formation of C3d is what is detected by the direct antibody test.

Cold agglutinin activity is determined by the thermal amplitude, which is the temperature range at which agglutination occurs. The upper threshold of this temperature is the most critical information for pathogenicity.

What other clinical manifestations may help me to diagnose cold agglutinin disease?

Acrocyanosis upon exposure to the cold is a clear associated symptom, while shortness of breath and fever may be symptoms in cases of post-infectious cold agglutinin disease. Signs and symptoms of anemia or hemolysis, such as shortness of breath, jaundice, and dark colored urine may also be present.

What other additional laboratory studies may be ordered?

A bone marrow biopsy should be performed to exclude an underlying lymphoproliferative disorder.

Furthermore, the following should be checked to assess for an underlying indolent lymphoma:

  • Serum protein electrophoresis

  • Serum immunofixation for monoclonal versus polyclonal differentiation

  • Kappa:lambda ratios

What’s the evidence?

Berentsen, S, Beiske, K, Tennfjord, G. "Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features, and therapy". Hematology. vol. 12. 2007. pp. 361-370.

[A review of cold agglutinin disease that focus on pathogenesis, clinical features, link to lymphoproliferative disorders, and treatment options including the use of new therapies.]

Berentsen, S, Randen, U, Vgan, A. "High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease". Blood. vol. 116. 2010. pp. 3180-3184.

[A prospective multicenter trial in which 29 cold agglutinin patients are treated with fludarabine and rituximab. Twenty-one percent of patients achieved CR, defined by absence of anemia and hemolysis, complete resolution of clinical symptoms, undetectable IgM by SPEP and immunofixation, and absence of lymphoproliferation via flow cytometry, bone marrow evaluation, and immunohistochemistry. Fifty-five percent of patients achieved PR, defined by a stable increase of hemoglobin by at least 2g/dL or to the normal range, a decrease in IgM by at least 50% or to the normal range, clinical symptom improvement, and transfusion independence. Median response duration was over 66 months. The major toxicity was hematologic, with 41% of patients experiencing grade 3 to 4 hematological toxicities.]

Berentsen, S, Ulvestad, E, Gjertsen, B. "Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients". Blood. vol. 103. 2004. pp. 2925-2928.

[Prospective study of 27 patients treated with rituximab monotherapy. The overall response rate was 54%, with an 11 month median duration of response.]

Berentsen, S, Ulvestad, E, Langholm, R. "Primary chronic cold agglutinin disease: a population based clinical study of 86 patients". Haematologica. vol. 91. 2006. pp. 460-466.

[A retrospective population based study of 86 patients with CAD in Norway. Provides clinical and laboratory signs of disease and discusses the use of rituximab in treatment, with an overall 60% response rate.]

Crisp, D, Pruzanski, W. "B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins)". Am J Med. vol. 72. 1982. pp. 915-922.

[Additional study that provides clinical manifestations, as well as laboratory findings in patients with cold agglutinin disease. In all, describes the data seen in 78 patients and points out that diseases with persistent cold agglutinins range from benign autoimmune processes, to malignant lymphomas.]

Gertz, M. "Management of cold haemolytic syndrome". Br J Haematol. vol. 138. 2007. pp. 422-429.

[A review of all cold hemolytic syndromes. Provides information on treatment and offers clinical signs and symptoms of disease.]

Judd, WJ. "How I Manage Cold Agglutinins". Transfusion. vol. 46. 2006. pp. 324-326.

[Review article, gives information on clinical and laboratory findings. Also provides treatment recommendations.]

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