Cold agglutinin disease (CAD) is a rare form of hemolytic anemia provoked by exposure to cold temperatures. Accounting for approximately 15%-25% of all cases of autoimmune hemolytic anemia, CAD can predispose individuals to vasoconstriction, resulting in acrocyanosis of the skin and other vasospastic conditions such as Raynaud’s phenomenon. In contrast, frostbite is defined as direct tissue injury resulting from exposure to sub-freezing temperatures.  

A recent French case report, published in Medicina, followed an 83-year-old woman who was admitted to the hospital for progressive extremity cyanosis and fatigue after exposure to cold. The patient, whose medical workup ultimately led to a diagnosis of underlying CAD, developed severe anemia requiring blood products in addition to extremity amputation due to severe tissue necrosis. Despite aggressive interventions, the patient’s condition worsened and she eventually died one month after admission to the hospital. 

Hospital Presentation

The woman first presented to a local emergency department for evaluation of shortness of breath, fatigue, weakness, and progressive cyanosis of her hands and feet. She reported exposure to cold temperatures for a period of approximately 1 hour prior to the onset of her symptoms, however, she did state that she had been wearing protective clothing while outdoors.

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On physical examination, the patient was found to have extensive cyanosis of both hands and feet with areas of tissue necrosis noted to her fingers and toes. Her vital signs were significant for a heart rate of 130 beats per minute but she was otherwise hemodynamically stable, according to the case study authors.

The patient’s blood tests were significant for hemoglobin (Hb) of 7.6 g/dL along with an elevated reticulocyte count and elevated LDH levels—suggestive of acute hemolysis. Coombs testing was performed, given the associated anemia, which confirmed the diagnosis of CAD. The patient was subsequently admitted to the hospital service for further management. 

Hospital Course 

Despite treatment with vasodilators and anticoagulation, the patient’s necrotic lesions worsened. She was evaluated by the hospital’s surgical services and the decision was made to amputate. The patient received plasma exchange to remove pathologic immunoglobulin and she also underwent treatment with rituximab and bendamustine following surgery. She also received an additional blood transfusion due to persistently low blood counts.

Given the severity of the patient’s cutaneous manifestations, additional testing was performed to evaluate for other underlying etiologies. As the case review authors note, up to 50% of patients diagnosed with CAD have an abnormal bone marrow B-cell clone and meet diagnostic criteria for lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM). Flow cytometry was performed on the patient and was found to be consistent with lymphoplasmacytic lymphoma, according to the case study authors. The MYD88 L265P mutation found in the majority of cases of LPL/WM was not demonstrated in the patient’s CAD-associated lymphoproliferative disease (LPD).

The patient’s postoperative course was complicated by recurrent bleeding at the amputation sites, requiring evacuation of several hematomas. The patient’s necrosis continued to progress and she declined further surgical interventions given her multiple comorbidities and the risks associated with further surgery. Supportive care was initiated and the patient died after a month-long hospitalization. 

Severe Cutaneous Findings in CAD

Although cutaneous findings in CAD such as acrocyanosis have been reported in up to 90% of individuals with the disease, severe clinical features such as necrosis, gangrene, and livedo reticularis are less common. 

Severe cases of acrocyanosis resulting in tissue necrosis and amputation have been noted in previous case studies, however. A 2014 report published in The Netherlands Journal of Medicine followed a 76-year-old male who presented to a local emergency department with black, discolored fingers believed to be due to severe acrocyanosis. Further testing confirmed cold antibodies and the patient was diagnosed with CAD. Despite treatment with rituximab, the patient’s fingers required amputation due to the severity of the tissue injury.

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The rapid clinical deterioration of the patient in the French case study was believed to be a result of a direct frostbite injury exacerbated by underlying CAD. The coexistence of these 2 entities was believed to have a synergistic effect—potentially leading to a worse outcome.   

“Frostbite and CAD require early identification and treatment to improve outcomes,” the case study authors noted. “Regarding the management of CAD patients, early diagnosis of CAD and prevention of CAD attacks such as acrocyanosis and subsequent hemoglobinuria are crucial in avoiding critical complications.” 


Lorenzo-Villalba N, Andres E, Guerrero-Niño J. Frostbite and cold agglutinin disease: coexistence of two entities leading to poor clinical outcomes. Medicina (Kaunas). 2021;57(6):592. doi:10.3390/medicina57060592

De Witte MA, Determann RM, Zeerleder SS. A man with ‘black fingers’. Neth J Med. 2014;72(1):35-40.