A Rare Case of Cold Agglutinin Mediated Hemolytic Anemia, Thrombocytopenia, Acute Renal Failure, and Venous Thromboembolism Due to Mycoplasma Pneumoniae infection: A Toxic Combination
Authors: Khan Marina , Agudile Emeka P. , Bashar Masharib , Stanoszek Lauren M , Assaly Ragheb , Hamouda Danae M 
Published: December 2024

INTRODUCTION:
Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia (AIHA) mediated by cold agglutinins (CAs) which mostly consists of immunoglobulin M that transiently binds to red blood cells (RBC) in peripheral circulation at lower temperature and this leads to activation of C3b complement mediated hemolysis. CAD can be primary, not associated with other diseases; and a secondary type, related to an underlying disease such as infections (viral or bacterial), lymphomas or immune disorders.
Some of the specific disease conditions that are implicated in secondary cold agglutinin hemolytic anemia (CAHA) include infections (e.g. Mycoplasma pneumonia), malignancies (e.g. lymphoma), and immune disorders (e.g. SLE). We report a rare case of CAHA, complicated by disseminated intravascular coagulation, acute renal failure and venous thromboembolism in a patient with Mycoplasma pneumoniae infection.
CASE PRESENTATION:
59-year-old male presented with shortness of breath, cough and right calf pain for 2 weeks with oxygen saturation of 86% on room air. Laboratory evaluation showed Hb of 11.3 g/dL, and a WBC of 13.95 K/uL. CTA showed submassive PE bilaterally, and multifocal pneumonia. Mechanical thrombectomy was performed due to hemodynamic instability and he was placed on heparin infusion. There was a sudden drop in platelets from 241K/uL to 19K/uL, hemoglobin dropped to 6.5 g/dL and leukocytosis up to 21K/uL. Respiratory panel was positive for Mycoplasma. INR was elevated to 2.29, APTT to 55 sec, and fibrinogen decreased to less than 60 mg/dL, suggestive of DIC. Haptoglobin was undetectable, and LDH was elevated to 1300 U/L indicating extravascular and intravascular hemolysis. A peripheral smear showed RBC agglutination concerning for CAHA due to Mycoplasma infection. The patient received treatment with cryoprecipitate, FFP and PRBC, and doxycycline. Subsequently, his renal function worsened with creatinine up to 4.3 mg/dL with declining urine output. He was initiated on hemodialysis. Cold agglutinin titer was high at 1:512. Plasmapheresis was performed eventually. His lab parameters improved including Hb up to 9.1g/dl, platelets up to 162 K/uL, fibrinogen up to 400 mg/dL, LDH down to 392 U/L, but his haptoglobin remained undetectable. Also, his urine output improved, but he remains on intermittent hemodialysis.
Despite stable blood counts, his labs consistently displayed high cold-agglutinin titers, low haptoglobin, and concerns about compensatory hemolysis. A decision is made to start the patient on sutimlimab (complement C1s inhibitor), and pneumococcal and meningococcal vaccinations are administered in preparation for the sutimlimab therapy.
Discussion:
Only a few case reports of secondary CAHA have been described in the literature. About 25% of patients with M.pneumoniae infection develop complications including AIHA. The pathophysiology of M. pneumoniae-associated CAHA is thought to be an autoimmune disorder where antibodies are directed against the I antigen, present on the surface of RBCs and ciliated cells of the bronchial epithelium. The binding of cold agglutinins to RBCs is triggered by low temperatures and leads to complement-mediated hemolysis.
The binding of IgM to RBCs activates the classical complement system and leads to the formation of C5b-C9 membrane attack complex and intravascular hemolysis. Alternatively, C3b-bound RBCs are opsonized, which increase phagocytosis in the liver and spleen, leading to extravascular hemolysis. Furthermore, a high level of cold agglutinin antibody titer goes further to support the diagnosis.
Treatment for M. pneumonia induced CAHA is mostly supportive, including keeping the patient warm and transfusion support with blood warmer. Antimicrobial treatment of the underlying mycoplasma infection has been shown to lead to rapid resolution of the CAHA. Corticosteroids, cytotoxic medications, and plasmapheresis are of limited value in secondary CAHA, but may be recommended in refractory cases.
Conclusion:
CAHA is a rare disorder that may occur in patients presenting with M. pneumoniae infection. It is, therefore, imperative to have a high index of suspicion in patients presenting with pneumonia and hemolysis, so as to ensure early diagnosis and prompt treatment.