Chronic Cold Agglutinin Disease: A Rare Hematologic Condition

By SWA S. W. Alexander July 23, 2025

Chronic Cold Agglutinin Disease (CAD) is a rare autoimmune hemolytic anemia that typically occurs in the context of B-cell lymphoproliferative disorders.

Vascular Spasms in the Extremities: A Source of Intense Pain
Vascular spasms in the arms or legs can cause severe, often excruciating pain due to the sudden narrowing of blood vessels, which restricts blood flow and oxygen delivery to tissues.

Symptoms of Circulatory Disorders
The symptoms of circulatory disorders vary depending on the affected area of the body and can range in intensity. Common signs include:

Leg Pain (Peripheral Arterial Disease): A hallmark symptom is pain during physical activity, such as walking or climbing stairs—a condition known as intermittent claudication. This discomfort typically subsides with rest, only to return with exertion.

It is characterized by the destruction of red blood cells (erythrocytes) triggered by cold temperatures. Although CAD often develops secondary to underlying conditions such as B-cell lymphomas, there also exists a rare idiopathic form that is primarily seen in elderly individuals. This idiopathic variant is considered a distinct lymphoproliferative disorder.

Unlike Waldenström’s macroglobulinemia, another condition marked by monoclonal gammopathy, idiopathic CAD lacks the MYD88 L265P mutation, which is a hallmark of Waldenström’s disease. This genetic distinction is crucial for differential diagnosis and subsequent treatment planning.

Cold Exposure and Associated Health Risks

Cold weather has measurable effects on human physiology. For each degree drop in external temperature, blood pressure can increase by approximately 0.1 to 0.2 mmHg. This is due to vasoconstriction, a narrowing of blood vessels near the skin surface, which helps conserve body heat but also leads to increased urine output (cold diuresis) and elevated blood viscosity. These changes significantly raise the risk of serious cardiovascular events such as thromboembolism, stroke, and myocardial infarction (heart attack).

Autoimmune Hemolytic Anemia and Its Triggers

One of the primary mechanisms in CAD is autoimmune hemolytic anemia (AIHA), where the immune system erroneously targets and destroys the body’s own red blood cells. This condition can be idiopathic or associated with other diseases such as systemic lupus erythematosus (SLE) or lymphomas, and may even be drug-induced, for example through penicillin use.

In AIHA, although the bone marrow compensates by increasing red blood cell production, these cells are prematurely destroyed, leading to symptoms like fatigue, pallor, and shortness of breath on exertion.

Diagnosing Cold Agglutinin Disease

The hallmark symptom of CAD is acrocyanosis, a bluish discoloration of the extremities such as fingers, toes, ears, or nose when exposed to cold. This symptom is reversible upon warming. In some cases, Raynaud’s phenomenon—where blood flow to extremities is drastically reduced due to cold or stress—may also be present.

Common signs of anemia, including fatigue, headaches, tachycardia, dizziness, and dyspnea on exertion, are frequently reported in patients. Diagnosis often involves blood tests revealing cold agglutinins (autoantibodies that clump red blood cells at low temperatures), elevated IgM levels, and sometimes monoclonal gammopathies.

Interpreting Elevated IgG and Monoclonal Gammopathies

Abnormally high levels of IgG may indicate a monoclonal gammopathy, a condition where a single clone of plasma cells produces large amounts of one type of immunoglobulin. This can be a sign of plasma cell disorders such as IgG myeloma, or reflect autoimmune diseases, chronic infections, or severe liver disease. Such findings warrant further investigation to distinguish between benign and malignant causes.

Conclusion

Chronic Cold Agglutinin Disease is a complex disorder with both autoimmune and hematologic characteristics. While rare, it poses significant diagnostic and therapeutic challenges. Early recognition of its symptoms—especially acrocyanosis and cold-induced hemolysis—is critical. Management typically includes avoiding cold exposure, treating underlying conditions like lymphoma, and in some cases, immunosuppressive therapies.

As our understanding of lymphoproliferative disorders deepens, the diagnostic and therapeutic strategies for CAD continue to evolve, offering hope for better outcomes in this challenging disease.