Autoimmune hemolytic anemia (AIHA)  is a disease in which antibodies attack the surface of erythrocytes. In about 70% of cases, autoantibodies react at body temperature and are hence classified as warm agglutinins. Cold agglutinins, on the other hand, cause hemolysis at cold temperatures. 

In AIHA, the complement system is known to be activated. Complement-induced hemolysis has been linked with thrombophilia. Studies have demonstrated that patients with either warm AIHA or cold agglutinin disease—both subtypes of AIHA—are at an increased risk of developing thromboembolic events. 

“According to the literature, 11% up to 27% of patients with AIHA suffer from thromboembolic events,” Schär and colleagues wrote in the European Journal of Haematology. “In a collective of patients with cold agglutinin disease, 7.2% suffered from thromboembolic complications as compared with 1.9% in healthy controls after one year and 11.5% versus 7.8% after 5 years, respectively.” 

Continue Reading

Due to mounting evidence of the association between AIHA and thromboembolic events, physicians are increasingly taking prophylactic action to prevent one from occurring. However, there are scarce guidelines on the stratification of thromboembolic risk in AIHA patients or the best method to achieve antithrombotic prophylaxis when anemia is present. 

Pulmonary Embolism in an AIHA Patient

In TH Open, Solari and colleagues described the case study of a patient with AIHA who was diagnosed with pulmonary embolism. 

The case involved a 75-year-old man who presented with dyspnea that had become progressively worse over the last month. His dyspnea was classified as New York Heart Association III (NYHA-III). Upon examination, the patient was afebrile, had chest pain under effort, and did not have a cough. 

Read more about cold agglutinin disease etiology 

The patient revealed that he suffered from severe generalized weakness, jaundice, and dark-colored urine 3 days prior. He was on medication for chronic obstructive pulmonary disease (COPD) and chronic ischemic heart disease and had undergone a double coronary artery bypass graft in 2006. 

Laboratory findings revealed normochromic, macrocytic anemia. Direct antiglobulin test revealed that the patient was strongly reactive for warm IgG1 and IgG3. Peripheral blood smear revealed orthochromatic erythroblasts, normal erythrocytes, microspherocytes, and polychromatic erythrocytes. 

The patient was diagnosed with warm AIHA. Workup for an underlying cause did not reveal anything. However, CT scan revealed a pulmonary embolism, and the patient’s diagnosis was revised to primary warm AIHA with concomitant pulmonary embolism. 

The patient was transfused with 1 unit of packed red blood cells and prescribed oral prednisolone (1.5 mg/kg per day). On day 9, he received 2 intravenous steroid pulses (methylprednisolone of 125 mg) due to ongoing hemolytic anemia. The patient was also prescribed the anticoagulant rivaroxaban at a dose of 15 mg twice daily for the first 21 days and 20 mg per day afterward. On day 13, the patient was discharged with corticosteroid tapering and rivaroxaban. 

Understanding the Risk Factors 

In PLOS One, Audia and colleagues conducted a study to better understand the risk factors that might lead to venous thromboembolic events in patients with AIHA. Their study included 48 patients with warm AIHA. 

“After a median follow-up of 24.8 months from warm AIHA diagnosis, 11 out of 48 patients (23%) had presented at least one [venous thromboembolic event],” they wrote. “At the time of [the venous thromboembolic event], active hemolysis was present in 10/11 patients (91%).” 

The proportion of patients with warm AIHA who experienced at least 1 venous thromboembolic event during the study period matched the 11% to 27% cited in other medical literature. 

Read more about cold agglutinin disease treatment 

In addition, the research team noted that the venous thromboembolic events experienced by study participants were consistent with pulmonary embolism in roughly half of the cases. However, symptoms of a pulmonary embolism, such as shortness of breath, can be mistakenly attributed to anemia, resulting in a misdiagnosis. 

In terms of the risk factors for the development of a thromboembolic event, the literature suggests that hemolysis itself is an independent risk factor. Since hemolysis is a defining characteristic of AIHA, patients with AIHA are naturally at a higher risk of developing a thromboembolic event. 

Audia and colleagues reported that certain laboratory findings are associated with a higher risk of developing a thromboembolic event. For example, higher total bilirubin levels and reticulocyte count were observed in patients who experienced a venous thromboembolic event. However, they did not find that patients who had more profound anemia upon diagnosis had an increased risk of developing such an event. 

In light of these findings, it is important that physicians take thromboprophylaxis seriously. However, some physicians might have reservations about prescribing anticoagulants in patients with anemia. 

“Although the reluctance to prescribe an anticoagulation therapy in patients with anemia is understandable, once the hemolytic etiology is confirmed, prophylactic anticoagulation should not be delayed, even in the absence of common [venous thromboembolic event] risk factors,” Audia and colleagues wrote. 

These sentiments were shared by Schär and colleagues, who wrote, “Due to the high incidence of [thromboembolic events] in patients with AIHA, prophylactic anticoagulation might be considered as soon as the diagnosis of AIHA is confirmed.”


Solari D, Alberio L, Ribi C, Grandoni F, Stalder G. Autoimmune hemolytic anemia and pulmonary embolism: an association to considerTH Open. 2021;5(1):e8-e13. doi:10.1055/s-0040-1721733

Schär DT, Daskalakis M, Mansouri B, Rovo A, Zeerleder S. Thromboembolic complications in autoimmune hemolytic anemia: retrospective studyEur J Haematol. 2022;108(1):45-51. doi:10.1111/ejh.13710

Audia S, Bach B, Samson M, et al. Venous thromboembolic events during warm autoimmune hemolytic anemiaPLoS One. 2018;13(11):e0207218. doi:10.1371/journal.pone.0207218