Cold agglutinin disease coexisting with left main coronary artery involvement and ventricular dysfunction — a challenging triad

Abstract

Cold hemagglutinin disease (CHAD) is a rare autoimmune condition characterized by cold-reactive antibodies causing hemagglutination and complement-mediated hemolysis. This case report details the successful management of a 56-year-old male with CHAD, coronary artery disease, and left ventricular dysfunction. The patient underwent coronary artery bypass grafting (CABG) amid challenges, including a rapid drop in hemoglobin levels, limited compatible blood supply, and cardiac comorbidities. Treatment involved rituximab, bortezomib, and a meticulous perioperative protocol to prevent hypothermia. The multidisciplinary approach, including hematologists, anesthetists, and surgeons, played a crucial role in managing the triad highlighting the importance of tailored management in CHAD cases.

Introduction

Cold hemagglutinin disease (CHAD) is an autoimmune condition resulting from cold-reactive antibodies, leading to hemagglutination and complement-mediated hemolysis when the body temperature drops. This poses considerable complications for patients undergoing cardiac surgery with hypothermia [1]. Here, we present a case of successful treatment for CHAD coexisting with coronary artery disease and left ventricular dysfunction.

Case report

A 56-year-old male, with no history of diabetes or hypertension, experienced fever followed by acute coronary syndrome. He was diagnosed as non-ST-segment elevation myocardial infarction (NSTEMI), underwent coronary angiography, and was referred for coronary artery bypass grafting (CABG) surgery. Echocardiography revealed moderate left ventricular systolic dysfunction with ejection fraction of 35% and mild mitral regurgitation. As per records, the patient presented with a hemoglobin of 9.1 g/dL during the coronary angiography. Subsequent to the pre-surgical evaluation, there was a notable drop of 3 g/dL in hemoglobin within 48 h and there was no compatible blood available on cross-match.

Patient was evaluated for hemolytic anemia and hemolytic markers were positive (indirect bilirubin 2.24 mg/dL, LDH (lactate dehydrogenase) 506 IU/L, reticulocyte count 9.1%, and creatinine 1.6 mg/dL). Polyspecific direct antiglobulin test (DAT) was positive, following which he was started on methylprednisolone 500 mg/day for 4 days and later on prednisolone at 1 mg/kg/day. A monospecific DAT conducted 48 h later was positive for C3d and negative for immunoglobulin G (IgG), suggesting cold hemagglutinin disease.

Cold agglutinin (CA) titer was 1:256 with thermal amplitude of 30 °C. However, there was no clinical evidence of a clonal disease (no lymphadenopathy or hepatosplenomegaly) except pallor and icterus.

A detailed investigation including contrast-enhanced computerized tomography (CECT) of the chest and abdomen was unremarkable. Antinuclear antibody immunofluorescence test, paraprotein workup including serum protein electrophoresis, immunofixation, and serum-free light chain analysis showed no abnormalities. Bone marrow aspirate and biopsy revealed erythroid hyperplasia with no signs of any clonal disease (Fig. 1).

Fig. 1.

The peripheral smear (A, B) and bone marrow (C, D) slides. A Red cell agglutination is seen in a background of normal white blood cells and platelet counts (× 100, Leishman stain), B higher magnification showing agglutination (× 400, Leishman stain); C bone marrow is cellular with presence of trilineage haematopoiesis (× 40, Leishman stain); D erythroid hyperplasia is seen and no atypical cell in the smear (× 400, Leishman stain)

Patient was started on rituximab 375 mg/m² weekly for 4 weeks. Meanwhile, we witnessed a drop in hemoglobin levels, reaching as low as 5.3 g/dL. Plasmapheresis as a rescue option was discussed, but considering the combination of cardiac comorbidities and unavailability of compatible blood, the plan was withheld. Intravenous immunoglobulin was also discussed but due to cost issues, it was reserved if there was a further drop in hemoglobin. Bortezomib, a proteosome inhibitor with anti-plasma cell activity, was administered at a dose of 2 mg once a week, sandwiched between rituximab doses, and four doses of the same were administered (Fig. 2). Steroid was tapered, considering a limited role in CHAD. The dose was reduced to 0.5 mg/kg from day 21, and 0.25 mg/kg from day 29; and was completely tapered off by day 42. Following the administration of the first dose of rituximab and bortezomib, there was a gradual ascent in hemoglobin levels and by the completion of the four doses, the hemoglobin level of 12.1 g/dL and CA titers of 1:32 were attained.

Fig. 2.

The trends in hemoglobin levels (blue line) and administration of methylprednisolone (green arrows), rituximab (orange arrows), and bortezomib (blue arrows) during different phases of treatment. Red dots indicate the leuco-reduced blood transfusion in the post-operative period. DOS, date of surgery; POD, postoperative day; ABG, arterial blood gases

The patient was further scheduled for CABG and blood investigations showed a hemoglobin level of 12.1 mg/dL, a hematocrit of 38.6%, a total leukocyte count of 8080/µL, platelet count of 176,000/µL, lactate dehydrogenase level of 256 IU/L, and a reticulocyte count of 9.2%.

Patient was put on prophylactic gram positive and gram-negative antibiotics coverage in view of the compromised state. To prevent hypothermia, a strict protocol was followed throughout the surgery: the operating room temperature was kept at around 25 °C before the patient’s arrival, the patient was covered with a blanket and cap during transfer, and a forced air warming system (Bair Hugger) along with a hot water blanket regulated at 37 °C using a Hemotherm was employed during the procedure.

The patient was connected to an active humidifier system with a closed circuit for anesthesia, ensuring that the delivered gases were maintained at approximately 37 °C. The administration of blood products and intravenous fluids was conducted through a blood warmer. These measures, along with continuous nasopharyngeal temperature monitoring, ensured that the temperature was maintained above 37 °C throughout the surgery. Off-pump CABG (without cell saver) was done using the left internal mammary artery to the left anterior descending artery, the radial artery to the left-sided target vessels, and the reverse saphenous vein to the posterior descending artery. No intraoperative blood transfusion was required (estimated blood loss around 350 mL), and no evidence of intraoperative hemolysis was encountered.

After shifting to intensive care unit (ICU), the patient’s initial arterial blood gas analysis revealed a hemoglobin level of 7.8 mg/dL. Subsequent administration of 1 unit of leuco-reduced red blood cells via a blood warmer channel resulted in the recovery of hemoglobin levels to 13.3 mg/dL. The patient remained stable and was successfully extubated on the same day. On postoperative day 1, his hemoglobin level was 10.8 mg/dL, bilirubin was measured at 2.28 mg/dL, reticulocyte count was 3.2%, and LDH was 395 IU/L. On the second postoperative day, hemoglobin levels dropped to 7.5 mg/dL, prompting transfusion of 2 units of leuco-reduced red blood cells using a similar approach. Concurrently, CA titers were assessed, revealing a titer of 1:8, reticulocyte count of 4%, and LDH 343 IU/L, and bilirubin was 0.85 mg/dL, indicating no hemolysis. Urine routine microscopy indicated a significant presence of red blood cells, possibly traumatic, explaining the blood loss. This was potentiated by dual antiplatelets and we transitioned to single antiplatelet regimen until the hematuria resolved. Given the ventricular dysfunction, the patient was maintained in a euvolemic state. By the fifth day, the hemoglobin level recovered to above 10 mg/dL with grossly clear urine, prompting a switch to dual antiplatelet regimen. The patient was discharged with cardiac medications. Steroid was completely tapered off within 7 weeks. Two months after initial diagnosis of CHAD and 1-month post-surgery, patient is clinically stable with hemoglobin above 12 g/dL.

Discussion

CHAD is a rare condition, and benign CA, although a variant of normal, rarely is detectable on routine screening. CHAD is responsible for 16 to 32% of all autoimmune hemolytic anemias in both children and adults, with a prevalence of 10 to 16 cases per 1 million people [2]. CHAD may be a primary disorder or be secondary to malignancy (most commonly lymphoma), infection (infectious mononucleosis or Mycoplasma pneumonia infection), or autoimmune diseases [3].

The significance of CAs is contingent on two factors: the plasma concentration and the thermal range at which hemagglutination takes place. Healthy individuals typically exhibit low levels of CAs in their sera, approximately 1:16; nevertheless, elevated titers increase the likelihood of CA activation [3]. Careful temperature monitoring must be undertaken at all levels to avoid CA activation causing catastrophic hemagglutination and hemolysis.

Managing CHAD is challenging as steroid, one of the most important drugs to treat autoimmune hemolytic anemia (AIHA), does not work well in cold agglutinins. It is a common practice to start steroid as soon as AIHA is suspected. In warm AIHA, the same is tapered off very slowly over several months. However, there is limited use of steroid in CHAD, and the same was rapidly tapered off in this case. The only reason of not totally stopping steroid was some lab evidence of reduction of blood incompatibility on cross-match after the pulse steroid administration, even before the first dose of other therapies was administered. As CA is immunoglobulin M, the same can be removed through plasmapheresis, but this is challenging, particularly in the presence of low hemoglobin, ventricular dysfunction, and left main disease. There is no compatible blood available to prime the circuit and transfusion of least incompatible blood may always be at risk of a haemolytic crisis and antecedent renal shutdown. The same may become catastrophic in the background of cardiac comorbidities. Maintaining a warm environment is also a challenge. Efficacy of rescue therapy with intravenous immunoglobulin is reported in CHAD [4].

Upstream complement inhibition by sutimlimab, a C1 inhibiting monoclonal antibody, is an option but availability of the same is an issue [5]. Rituximab, an anti-CD20 monoclonal antibody is an important agent which help in reducing the antibody titers and help in controlling the hemolysis. This agent is administered at a standard dose of 375 mg/m² on days 1, 8, 15, and 22. In a prospective study of 27 patients of CHAD, 54% patient showed response to rituximab. Responders showed a 4 g/dL increment in hemoglobin, with a median time to response to 1.5 months and a median duration of response of 11 months [6]. In case a clonal disease is documented, the same can be combined with bendamustine or fludarabine, a form of chemotherapy, which improves the overall response rate to 78%, and a sustained remission of 77% over 5 years [7]. Anti-plasma cell therapy with a proteasome inhibitor like bortezomib or with anti-CD38 monoclonal antibody like daratumumab finds off-label use in autoimmune conditions. They are mostly considered in relapsed and refractory settings and evidences for the same are available only in the form of case reports [8, 9]. These agents, especially bortezomib, are safe, accessible, and affordable agents, with a reasonably good response rate. In this index case, we used this agent upfront in the treatment schema, mainly due to the safety concern and cost-related challenges in using the rescue treatment options like plasmapheresis and intravenous immunoglobulin. The results obtained were encouraging, signifying its use in upfront treatment setting may be a good therapeutic option in such cases. The use of such agents as frontline therapy in CHAD for a patient planned for CABG has not been reported in the literature to the best of our knowledge.

Managing a CHAD case requires careful consideration

• Anesthetic considerations

During general anesthesia, heat loss occurs mainly through radiation (up to 40%) and convection (up to 30%) [10]. Simple measures like employing warming mattresses and closed-circuit system of anesthesia and delivery of products using a fluid warmer should not be overlooked. Similarly, the operating room temperature should be maintained around 22 degree C.

• Surgical considerations

Irrespective of the technique employed, it is essential to limit systemic cooling during cardiopulmonary bypass, if used, so as to maintain the systemic perfusion temperature. Minimizing the surgical time is key to averting heat loss from the opened chest cavity.

• General considerations

The role of bortezomib and rituximab proved essential when other treatments were not viable. They played a key role in managing the patient’s critical preoperative state with cardiac comorbidities, effectively improving the cardiac condition to a point where surgery could be safely conducted.

Challenges encountered during the management of this case

On presentation, our patient had severe anemia, and there was a lack of compatible blood for cross-matching. The concurrent presence of coronary artery disease involving the left main and triple vessels, along with ventricular dysfunction, in association with this state, may precipitate heart failure and cardiac deterioration. Rituximab and bortezomib were promptly initiated in combination, but they can only supress new antibody production. The preformed antibody persists and continues to hemolysis. A combination of both the agents was used, considering the cardiac comorbidities, and an urgency to reduce the antibody production at the earliest in order to prevent use of a rescue therapy, administration of which had multiple challenges as discussed previously.

Several factors were instrumental in effectively handling the case and attaining a favorable result:

• Attaining the antibody titer below 1:64 prior to surgery.

• Employing off-pump CABG and improving temperature control for better maintenance at normothermia.

• Post-operative administration of blood if hemoglobin levels fell < 8 g/dL and using a fluid warmer for all necessary transfusions.

• Identifying the postoperative decrease in hemoglobin as attributable to catheter-related trauma rather than hemolysis.

With a confirmed diagnosis of cold agglutinin disease, the plan of care can be focused on measures to stabilizing the patient, maintaining normothermia throughout hospitalization, and administration of bortezomib and rituximab when other options seem not feasible.

Conclusion

Close monitoring for agglutination, aggressive management of hemolysis with rituximab, and judicious use of steroid/bortezomib may achieve rapid restoration of hemoglobin possibly avoiding risky transfusion and is essential to prevent life-threatening events. Maintaining a heightened sense of suspicion and actively involving the hematology team, implementing measures across perioperative stages, is essential for accurate diagnosis and effective management.

The multidisciplinary team approach is vital to deal with the disease during the perioperative period. Strict vigilance for agglutination, hemolysis, and end organ damage is required to avoid life-threatening events.

Author contribution

DS: Reviewed the final manuscript.

KG, AJ: Prepared the draft for manuscript and written the manuscript.

DN, CS: Given inputs for manuscript editing and changes.

Funding

None.

Declarations

Ethics approval

Not applicable.

Informed consent statement

Written informed consent was obtained from the patient for the publication of this case report and its accompanying images.

Conflict of interest

None.

Statement of human and animal rights

Not applicable.