Cold-induced erythrocyanosis and acrocyanosis

Specialty: Hematology.

• Raynaud's phenomenon due to cold agglutinins
• cryophilic acrocyanosis
• peripheral cyanosis due to cold antibodies

Why it occurs

• Primary or idiopathic cold agglutinin disease (autoimmune hemolytic anemia mediated by IgM antibodies that bind to antigen I on the erythrocyte membrane at optimal temperatures below 37 °C, typically in the capillaries of cold extremities, inducing red blood cell agglutination and partial complement activation)
• Infectious mononucleosis due to Epstein-Barr virus or atypical pneumonia due to Mycoplasma pneumoniae (transient infectious causes of self-limited polyclonal cold agglutinin production)
• Splenic marginal zone lymphoma or other B cell lymphoproliferative neoplasms (clonal neoplastic production of monoclonal IgM with cold agglutinin activity)
• Mixed cryoglobulinemia type II and III (frequently associated with chronic hepatitis C virus infection, with deposition of circulating immune complexes sensitive to temperature)
• Severe primary Raynaud syndrome (as a non-hematological vasospastic differential diagnosis).

Initial workup

Quantitative determination of serum cold agglutinin titer (significant titers are typically >1:64 at 4°C); direct Coombs test (direct antihuman globulin) markedly positive for C3d (complement fraction) and classically negative or only weakly positive for IgG; peripheral blood smear made from a sample kept strictly at 37 °C to avoid in vitro agglutination of erythrocytes (massive aggregates of clustered red blood cells will be observed); complete blood count with erythrocyte indices (where agglutination can cause a false and extreme elevation of the mean corpuscular volume - MCV and the mean corpuscular hemoglobin concentration - MCHC, requiring preheating of the sample to obtain a true reading); serological screening for Epstein-Barr virus, Mycoplasma pneumoniae and hepatitis C virus.

Standard management

• Sutimlimab — selective monoclonal antibody directed against the serine protease C1s of the complement C1 complex; specifically inhibits the classical complement pathway, effectively preventing extravascular hemolysis and associated symptoms in cold agglutinin disease
• Rituximab — anti-CD20 monoclonal antibody; selectively destroys the clones of B lymphocytes that produce abnormal IgM, achieving prolonged clinical remissions in the primary variant or those associated with lymphomas
• Fludarabine associated with Rituximab — combined immunochemotherapy regimen for patients with severe cold agglutinin disease refractory to monotherapy
• Folic acid (oral supplementation at a dose of 5 mg daily to compensate for accelerated folate consumption due to compensatory erythropoiesis of chronic hemolysis).