In Acta Hematologica, Gelman and colleagues describe the case of a patient with cold agglutinin-mediated autoimmune hemolytic anemia associated with antiphospholipid syndrome. 

The 43-year-old woman presented with worsening fatigue and bilateral knee pain over the last 2 weeks. It is important to note she was a habitual heavy smoker. Laboratory results confirmed severe anemia (hemoglobin: 6.4 g/dL).

During the patient’s presentation and subsequent investigation, the temperature outdoors ranged between 23°C and 32°C. Further medical history revealed that she suffered from a single case of low-grade fever (37.5°C) during the preceding months. She also suffered from mild weight loss and had developed pancytopenia 2 years prior.

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Physicians discovered transient elevations in hepatocellular enzymes, as well as mild splenomegaly, and a computerized tomography scan confirmed this. The physicians again discovered pancytopenia.

The patient also had elevated lactate dehydrogenase, low levels of haptoglobin, and prolonged partial thromboplastin time. Urine tests ruled out proteinuria. Blood smears were highly suggestive of hemolysis. Direct antiglobulin test was positive for C3d but negative for IgM and IgG. 

Past medical records revealed that the patient was previously diagnosed with antiphospholipid syndrome, which was diagnosed following an ischemic cerebrovascular accident and 6 miscarriages. The patient was on warfarin, which achieved therapeutic internationalized normalized ratio (INR) values. 

“A bone marrow biopsy revealed an abundance of red cell precursors with a shift to the left and normal myeloid maturation; several clusters of small lymphoid cells, some staining positive for CD20+ and some for CD3+ were also present,” the authors of the study wrote. “Polymerase chain reaction for monoclonal B-cell gene rearrangement was negative, effectively ruling out the presence of a lymphoproliferative process.” 

The patient’s final diagnosis was IgM-mediated autoimmune hemolytic anemia (cold agglutinin disease) associated with antiphospholipid syndrome. Her physicians prescribed a short corticosteroid therapy, which did not help, but the patient’s hemoglobin levels remained stable throughout hospitalization. She was subsequently discharged with folate supplementation and anticoagulation. 

Read more about cold agglutinin disease etiology 

Upon discharge, the patient was treated with 2 units of packed red blood cells once a month during subsequent follow-ups. Eventually, her laboratory parameters improved. 

“On her third outpatient visit, 3 months following discharge she had a white blood cell count of 4,400 U/L, [hemoglobin] of 11.3 g/dL, and a platelet count of 70,000 U/L,” the authors of the study reported. 

Managing a Rare Combination

In the case of this patient, antiphospholipid syndrome was diagnosed before she presented with cold agglutinin disease. 

“Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity,” Sammaritano wrote in Best Practice & Research Clinical Rheumatology. 

The treatment options for antiphospholipid syndrome are diverse, depending on the most pressing concern at the time of diagnosis. “Treatment categories may be separated into primary thromboprophylaxis, secondary thromboprophylaxis, the treatment of [catastrophic antiphospholipid syndrome], pregnancy prophylaxis, and the treatment of noncriteria manifestations,” Sammaritano wrote. 

In the case study, physicians highlighted the importance of devising therapeutic decisions with the utmost care, such as choosing a suitable therapeutic strategy while being wary of the possibility of concurrent lymphoproliferative disease. This is because some reports suggest a link between antiphospholipid syndrome and hematological malignancy. 

The patient’s cold agglutinin disease diagnosis shouldn’t come as a surprise, since warm-type autoimmune hemolytic anemia in patients with antiphospholipid syndrome is rare. In fact, autoimmune hemolytic anemia in general is considered rare in patients with antiphospholipid syndrome. Some studies put the figure of autoimmune hemolytic anemia in patients with antiphospholipid syndrome at the 6.6% mark. Leukopenia is a hematological disorder much more commonly associated with antiphospholipid syndrome. 

Patients with primary antiphospholipid syndrome are often diagnosed with hypercomplementemia, which reflects the activation and consumption of the complement system. Through a series of mechanisms, this can contribute to the rise of thrombotic events. It is important to note that the hematological process underlying cold agglutinin disease is also complement-dependent. 

“The primary mechanism is activation of the classical complement pathway and extravascular hemolysis, though terminal complement cascade activation and intravascular hemolysis also exist in certain cases,” the authors of the study wrote. “The persistent complement activation and consumption cause low levels of C3 and C4 in [cold agglutinin disease] patients.” 

Read more about cold agglutinin disease treatment 

In rheumatology, antiphospholipid syndrome, particularly catastrophic cases, continues to be a significant cause of morbidity and mortality. Even patients on warfarin may experience recurrent thromboses, and maintaining a therapeutic range of INR remains a challenge. Hence, any cases of patients with antiphospholipid syndrome warrant aggressive therapy, with or without the presence of autoimmune hemolytic anemia. 

The main takeaway from this case study is that cold agglutinin disease can occur in the background of antiphospholipid syndrome. Both cold agglutinin disease and antiphospholipid syndrome are immune-mediated diseases. Could these conditions share a common etiology? Further research is needed to elucidate this possibility. 


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

Sammaritano LR. Antiphospholipid syndromeBest Pract Res Clin Rheumatol. 2020;34(1):101463. doi:10.1016/j.berh.2019.101463