vessel with red blood cells
Inside space of empty healthy human anatomical vessel with red blood cells – erythrocytes and endothelium cells, 3d rendering

Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease, with the clinical picture ranging from “mild/compensated to life-threatening anemia, depending on the antibody’s thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation,” Barcellini and Fattizzo wrote. One of the rare manifestations of AIHA is cold agglutinin disease (CAD). 

In Rare Disease Advisor, we have sought to cover CAD from as many varied angles as possible. Most cases of CAD are described in isolation or together with the suspected cause or trigger of the disease. 

Read more about CAD etiology 

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Gelman and colleagues wrote a case study of a woman who was diagnosed with CAD and antiphospholipid syndrome simultaneously. This is a unique case study; the authors explained, “While no clear association exists between these 2 entities, complement activation is known to occur in both of them . . . To the best of our knowledge, such an association has not been described thus far.” 

A ‘Unique Combination’ 

In the case report, Gelman and colleagues describe a 53-year-old woman who presented with worsening fatigue and bilateral knee pain. Initial laboratory workup revealed: 

  • White blood cell count: 2400 U/L (low) 
  • Hemoglobin: 6.9 g/dL (low) 
  • Platelet count: 94,000 U/L (low) 
  • Haptoglobin: 3 mg/L (low) 
  • International Normalized Ratio (INR): 2.66 ratio (high) 
  • Partial thromboplastin time (PTT): 53.5 s (high) 
  • C-reactive protein (CRP): 0.75 mg/dL (high) 
  • Direct antiglobulin test was negative for immunoglobulin M (IgM) and immunoglobulin G (IgG) and positive for C3d. 

Her chest X-ray was normal. Computed tomography (CT) of the chest, abdomen, and pelvis demonstrated splenomegaly only. No infection was detected. 

The patient’s past medical history revealed 6 miscarriages and an ischemic cerebrovascular accident, leading to a diagnosis of antiphospholipid syndrome. She was started on warfarin therapy and her INR values were within the therapeutic range. 

Read more about CAD diagnosis 

Upon physical examination, her spleen was palpable 2 cm below the costal margin. No further abdominal abnormalities were detected. Immune serologies revealed elevated antiphospholipid antibodies and IgM levels. The patient was eventually diagnosed with IgM-mediated AIHA in association with antiphospholipid syndrome. 

Throughout the patient’s hospital stay, the temperature outside ranged between 23 °C and 32 °C. She experienced a single episode of low-grade fever and mild weight loss during her hospital admission. The patient’s hemoglobin levels remained stable and she was discharged.

“Over the next 2 months, she was treated with 2 units of packed red blood cells on monthly outpatient follow-up visits, which led to gradual improvement in clinical symptoms and laboratory parameters,” the research team wrote. ”On her third outpatient visit, 3 months following discharge she had a white blood cell count of 4,400 U/L [normal], Hb of 11.3 g/dL [close to normal], and a platelet count of 70,000 U/L [low].” 

Gelman et al summarized their findings: “In this case report we describe a unique combination of APLS and [cold agglutinin] IgM-mediated AIHA, presenting as pancytopenia, DAT-positive hemolytic anemia, splenomegaly and low complement levels, without lymphadenopathy or evidence of clonal lymphoid-proliferation on bone marrow biopsy.” 

The Role of the Complement System 

Given that the complement system is activated in both CAD and antiphospholipid syndrome, let us explore it in a little more detail. 

In CAD, hemolysis is activated by the classical complement pathway. Gavriilaki and Brodsky, in their study on complementopathies and precision medicine, wrote, “The IgM cold agglutinin (IgM-CA) antibody activates the classical complement pathway. C1 esterase activates C4 and C2, ultimately generating the C3 convertase, which cleaves C3 to C3a and C3b.” 

The C3b-coated red blood cells are then sequestered predominantly in the liver by macrophages of the reticuloendothelial system. Next, surviving C3b of red blood cells are cleaved, leading to higher levels of circulating red blood cells with C3b on their surface, causing an increased risk of thromboembolism. 

Antiphospholipid antibody syndrome, on the other hand, “is an acquired thrombophilia characterized by thrombosis affecting the venous or arterial vascular systems and/or obstetrical morbidity with the persistent presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibody, and anti–β2-glycoprotein-I syndrome,” Gavriilaki and Brodsky wrote. 

Researchers have observed an increase in C5b-9, Bb fragments, and C3a in the serum of patients with antiphospholipid syndrome. Recent studies have demonstrated that anti-β2GPI antibodies activate the complement system in antiphospholipid syndrome. 

Given that the case study described in this article linked CAD with antiphospholipid syndrome in a single patient, is it possible that complement activation had something to do with both pathologies occurring simultaneously? The bad news is that we still don’t know enough about the complement system to give a definite answer; the good news is that the discovery of the role of the complement system in multiple pathologies opens the door for more targeted therapeutics to be developed in the future. 

Gavriilaki and Brodsky painted a picture of what is possible: “Potentially novel indications span various disciplines, including hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology . . . Improvements in genetic and functional assays coupled with numerous novel and highly specific complement inhibitors will only increase the personalized approach to treating complementopathies.” 


Barcellini W, Fattizzo B. The changing landscape of autoimmune hemolytic anemia. Front Immunol. Published online June 3, 2020. doi:10.3389/fimmu.2020.00946

Gelman R, Kharouf F, Ishay Y, Gural A. Cold agglutinin-mediated autoimmune hemolytic anemia in association with antiphospholipid syndrome. Acta Haematol. 2021;144(6):693-697. doi: 10.1159/000516295

Gavriilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest. Published online May 1, 2020. doi:10.1172/JCI136094