When a patient presents with multiple comorbidities, it is important to categorize them as being either acute or chronic. However, sometimes acute diseases exacerbate chronic ones and physicians have to make a difficult decision on the best treatment regimen for the patient. This is rarely straightforward and often requires multidisciplinary input. 

In some cases, the preferred course of treatment for an acute disease may be impeded by possible interactions with existing medications for chronic ones. Chronic diseases may also cause a patient to become immunologically vulnerable, disqualifying certain high-risk treatments. 

In all the permutations of possible outcomes for a patient with more than one disorder, it is important that physicians proceed with utmost caution. Failure to do so can allow any one disease to gain the upper hand and cause further damage. 

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In Case Reports in Oncology, Brage and colleagues presented one such case—a patient with newly diagnosed renal cancer who presented with cold agglutinin disease (CAD). 

Suspicion of Autoimmune Hemolytic Anemia 

The 67-year-old man presented with asthenia and colicky abdominal pain. He had been recently diagnosed with stage IV clear-cell renal-cell carcinoma and was awaiting the initiation of systemic treatment. The cancer had spread to his liver, bone, and lymph nodes, indicating a poor prognosis. 

Upon physical examination, the patient was noticeably pale. Laboratory tests demonstrated hypochromic-macrocytic anemia grade 4 (hemoglobin of 4.5 g/dL). His total bilirubin was 2.60 mg/dL (elevated) and lactate dehydrogenase was 340 U/L (elevated). 

Due to the patient’s severe anemia and abdominal pain, his physicians wanted to rule out any bleeding. A computed tomography scan ruled out active hemorrhage. 

A direct Coombs test returned positive (+4). The result of a monospecific study was also positive for anti-IgG (+2) and anti-C3bC3b (+4). 

“A cryoagglutinin study was also performed, including titration and temperature range (4°C, 22°C, and 37°C), being conclusive of cold agglutinin disease, with high levels in the parameters analyzed,” Brage et al wrote. 

Read more about CAD diagnosis 

Blood warmer transfusions were initiated. Other causes of autoimmune hemolytic anemia were ruled out, such as the presence of infection or lymphoproliferative disorders. His physicians started him on sunitinib at a dose of 50 mg/24 h (4:2 schedule) for his renal cancer. Four days later, his hemoglobin levels improved. He was discharged after 8 days of hospitalization. 

An Unusual Case Presentation

Around a third of patients diagnosed with CAD have hemoglobin levels of less than 8.0 g/dL. The rest have mild-to-moderate anemia, meaning they have hemoglobin levels between 10.0 g/dL and the lower limits of normal. 

In the case of this patient, his hemoglobin levels were 4.5 g/dL, which indicates severe anemia. However, the patient did not present with all the hallmarks of anemia; in addition, his symptoms would not normally lead to a suspicion of CAD. It was only after blood tests were carried out that his physicians conducted an investigational workup to determine the cause of his anemia. 

In colder climates, most patients with CAD present with ischemic symptoms. As a result of erythrocyte agglutination in the acral circulation, patients can present with Raynaud-like disease or acrocyanosis. In this case study, nothing in his medical history suggested that he experienced these symptoms. 

Further complicating this case was the fact that the patient was newly diagnosed with stage IV renal cancer but was still awaiting the initiation of systemic treatment. In the case study, as presented, no reason was given for this delay. 

Autoimmune hemolytic anemia can be a paraneoplastic syndrome and is most commonly associated with lymphoproliferative disorders, such as non-Hodgkin lymphoma. Studies have demonstrated that approximately 5.7% of patients with newly diagnosed autoimmune hemolytic anemia have an underlying neoplasm. 

However, autoimmune hemolytic anemia as a paraneoplastic syndrome rarely occurs in renal cancers. They are most frequently associated with Kaposi’s sarcoma and non-small cell lung cancer.

The patient’s physicians initiated sunitinib, a tyrosine kinase-targeted therapy, as systemic therapy for his renal cancer. The likely resulting decrease in tumor antigenic load led to vast improvements in the patient’s clinical condition within a few days. 

In the case of this patient, he was prescribed blood warmer transfusions for his CAD. There is no consensus on when CAD should be treated, since older therapies have been proven to be largely ineffective. In addition, his physicians considered the definitive management of the patient’s CAD to be the treatment of his underlying renal cancer. 

Read more about CAD treatment 

“In unselected descriptive series, 70% to 80% of patients with CAD have received therapy,” Berentsen wrote in Blood. “Not all treatments used in warm [autoimmune hemolytic anemia] are effective in CAD. Unfortunately, ineffective therapies are still prevalent worldwide.” 

The patient in this case study was not prescribed any additional treatment for his CAD except for blood transfusions. However, the prescription of sunitinib accelerated his recovery and he was discharged in about a week. 

The final diagnosis given by the patient’s physicians was “autoimmune hemolytic anemia due to cold antibodies as paraneoplastic syndrome in a patient with a recent diagnosis of metastatic clear-cell renal carcinoma.” 

In the case of this patient, although his acute issue (severe anemia) was resolved, his stage IV renal cancer still carried a poor prognosis and was likely to result in continued clinical deterioration. 


Terán Brage E, Fonseca Santos M, Lozano Mejorada R, et al. Autoimmune haemolytic anaemia due to cold antibodies in a renal cancer patientCase Rep Oncol. 2022;15(2):507-514. doi:10.1159/000524592

Berentsen S. How I treat cold agglutinin diseaseBlood. 2021;137(10):1295-1303. doi:10.1182/blood.2019003809