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Case Reports
7 May 2024

Severe, Refractory Primary Warm Autoimmune Hemolytic Anemia Requiring 90 Erythrocyte Transfusions

Publication: Annals of Internal Medicine: Clinical Cases
Volume 3, Number 5

Abstract

A previously healthy 60-year-old man presented to the hospital with a hemoglobin of 3.5 g/dL. He was diagnosed with severe warm autoimmune hemolytic anemia with reticulocytopenia on hospital day 1 that was not responsive to steroids, immune globulin, and rituximab. Over a 42-day hospital stay, the patient remained continuously transfusion-dependent with a 90 red cell unit requirement for his refractory disease. He was trialed on therapeutic plasma exchange before ultimately undergoing inpatient splenectomy that led to a response within hours. He remains in complete remission at 6 months of follow-up.

Background

Warm autoimmune hemolytic anemia (wAIHA) is caused by IgG antibodies directed against self-erythrocytes, causing mostly extravascular hemolysis by splenic macrophages (1). The condition can be primary (idiopathic) or, as in 50% to 60% of cases (2), secondary to autoimmune disorders, neoplasm, infection, or medications (3). A positive direct antiglobulin test in conjunction with clinical history and laboratory evidence of hemolysis makes the diagnosis. Predictors of disease severity include initial presenting hemoglobin 6 g/dL or less (4) and the ability of the bone marrow to compensate. Therapies to treat primary wAIHA are driven largely by expert opinion (5, 6), with a few prospective trials published (7, 8) and, as of 2023, no treatments approved by the Food and Drug Administration. The cornerstone of treatment remains glucocorticoid therapy. Rituximab is increasingly favored in concomitant first-line treatment (9), although the median time to response is 3 to 6 weeks. Splenectomy previously was considered a second-line therapy (10) and is effective, with long-lasting remission reported (9). However, because of perceived tripartite risk for infection, thrombosis, and perioperative mortality, splenectomy was recommended as a third-line treatment in recent guidelines (11). Supportive management includes red blood cell transfusion, intravenous immunoglobulin, folic acid supplementation, stimulation of bone marrow with recombinant erythropoietin, venous thromboprophylaxis, and vaccination (1, 12).

Objective

This case highlights the importance of early identification of primary wAIHA, adaptation to its severity, and the use of splenectomy in refractory disease.

Case Report

A healthy 60-year-old man presented to the hospital with jaundice, confusion, progressive fatigue, dark urine, and dyspnea on exertion. Ten days prior, he had a root canal procedure and started amoxicillin. Laboratory testing in the emergency department demonstrated a hemoglobin of 3.5 g/dL (reference: 13.2–17.1 g/dL) and a positive direct antiglobulin test for IgG and negative for C3 (as well as a panagglutinin in elution studies), before emergent red blood cell transfusion with the least crossmatch-incompatible units. A diagnosis of wAIHA with associated reticulocytopenia (absolute reticulocyte count of 0.002 × 106 cells/μL; reference: 0.023–0.140 × 106 cells/μL) was made, and the patient had a thorough work-up for secondary causes, as shown in Table 1, that was negative.
Table 1. Diagnostic wAIHA Work-up, Results, and Interpretation of the Studies
CategoryLaboratory TestResultReference With UnitsDate ObtainedDate ReportedInterpretation
Primary wAIHADATDAT IgG 2+
DAT C3 negative
Negative
Negative
D1D1wAIHA
SLE/autoimmuneANA*<1:80NegativeD1D6Negative
Lupus anticoagulant1.10<1.2D6D8Negative
Anticardiolipin antibodyIgG 4.4
IgM 72
<10 GPL U/mL
<10 MPL U/mL
D6D7IgM positive, but IgG negative. Per rheumatology colleagues, IgG usually positive and combined with clinical picture of lack of venous thromboembolism, APS was not suspected.
Anti-B2gpl antibodyIgG 3.4
IgM 16
<7 U/mL
<7 U/mL
D6D7IgM positive, but as above.
ComplementC3 95
C4 12
90–180 mg/dL
10–40 mg/dL
D6D6Normal
Lymphoma and other solid tumorsSPEP*Discrete abnormal band measuring 0.2 g/dL present in the gamma region D1D2Query bone marrow aspiration and biopsy (MGUS versus more)
IFE*Faint, possibly abnormal band detected in the gamma region in serum and best characterized as IgG kappa. D1D8Query bone marrow aspiration and biopsy (MGUS versus more)
Serum-free kappa lambda light chains with ratioKappa free light chains 2.97
Lambda free light chains 1.92
Kappa/Lambda free light chains ratio 1.55
0.33–1.94 mg/dL
0.57–2.63 mg/dL
0.26–1.65 mg/dL
D1D1Elevated kappa free light chain, but normal ratio. Query bone marrow aspiration and biopsy (MGUS versus more).
immunotyping of B-lymphocytes from peripheral blood*No circulating CD34+ CD117+ blasts detected. Mature myeloid elements demonstrate a normal, although slightly left-shifted, CD10/CD11b/CD13/CD16/CD33 pattern. PNH clone is absent. Granulocytes and monocytes show normal expression of GPI-linked markers CD16, CD24, and CD14 with normal FLAER binding. Erythrocytes show normal expression of CD59. There is no abnormal immunophenotype T cell population suggestive of T-cell lymphoproliferative disease, including no increase in T-LGLs. D1D2No evidence of monoclonal non-Hodgkin B-cell lymphoproliferative disease. No PNH. No T-cell lymphoproliferative disease.
CT scan (CAP)*No thoracic or abdominopelvic findings, without significant lymphadenopathy. D1, D4D1, D5Normal. No evidence of malignancy.
Bilateral lower extremity venous Doppler ultrasoundNo evidence of deep venous thrombosis of the bilateral lower extremities. D4D4Normal. No evidence of deep vein thromboses.
Bone marrow aspiration and biopsyHypercellular erythroid-predominant marrow showing maturing trilineage hematopoiesis with erythroid left-shift D7D15No evidence of primary bone marrow process.
Primary immunodeficiencyIgA, IgG, IgM levels*IgM 175
IgA 151
IgG 2320
IgG 1 644
IgG 2 401
IgG 3 40
IgG 4 17.5
IgG total 1137
40–230 mg/dL
70–470 mg/dL
700–1600 mg/dL
382–929 mg/dL
242–700 mg/dL
22–176 mg/dL
3.9–86.4 mg/dL
700–1600 mg/dL
D1D1Normal levels, IgG elevated in setting of autoantibody. IgG subclasses normal.
InfectionHIV, hepatitis C, hepatitis B tests*HIV Ab with Ag negative
Hepatitis A IgM negative
Hepatitis B core IgM negative
Hepatitis B surface Ag negative
Hepatitis B core Ab negative
Hepatitis B surface Ab negative
Hepatitis C Ab negative
Negative
Negative
Negative
Negative
Negative
≥12 mIU/mL
Negative
D1D1, D2Hepatitis B nonimmune. No serologic evidence of acute infection.
CMV, parvovirus-B19, EBV IgM, IgGCMV IgM < 8
CMV IgG < 0.20
EBV IgM 21.8
EBV IgG 292
Parvovirus IgM, IgG negative
Parvovirus DNA PCR negative
<30 AU/mL, <0.59 U/mL
<35 U/mL
<22 U/mL
Negative
Negative
D1
D5
D1
D6
Exposed to EBV previously, but no active infection.
 Babesia, Ehrlichia, Anaplasma negative; treponema negativeNegativeD9D11Tickborne disease and syphilis negative.
MedicationsDrug-dependent antibodyAmoxicillin IgG, IgM both negativeNegativeD5D18No antibodies to amoxicillin, suggesting this was not the trigger.
ANA = antinuclear antibodies; APS = antiphospholipid syndrome; SPEP = serum protein electrophoresis; IFE = immunofixation; CMV = cytomegalovirus; CT = computed tomography; DAT = direct antiglobulin test; EBV = Epstein–Barr virus; MGUS = monoclonal gammopathy of undetermined significance; PCR = polymerase chain reaction; PNH = paroxysmal nocturnal hemoglobinuria; SLE = systemic lupus erythematosus; wAIHA = warm autoimmune hemolytic anemia.
*
Recommended laboratory testing for secondary wAIHA per the Autoimmune Hemolytic Anemia First International Consensus statement.
Parallel to this extensive work-up, the patient was immediately started on treatment, as listed in Table 2. He began steroids (day 1), initially with prednisone, 140 mg daily (1 mg/kg) for 1 week, along with intravenous immunoglobulin, 1 g/kg for 2 days (days 1 and 2). An erythropoietin (EPO) level was drawn and recombinant EPO administered on hospital day 3 (12). Further doses were canceled once the endogenous EPO level returned at 690.6 mU/mL (reference: 3–18 mU/mL). With lack of stabilization of hemoglobin despite upfront steroids, rituximab was initiated on day 4, as seen in Figure 1. The patient's other cell counts decreased in parallel with the anemia—at its nadir, on day 6, the leukocyte count was 0.5 × 103/μL (reference 4–11 × 103/μL with an absolute neutrophil count of 0.15 × 103/μL (reference: 2.0–7.6 × 103/μL) and platelets 22 × 103/μL (reference: 150–420 × 103/μL). A bone marrow biopsy done on day 7 was negative. Treatment was then intensified with pulse dose methylprednisolone on day 9 for 4 days. The leukocyte, absolute neutrophil, and platelet counts recovered, although the anemia persisted. Laboratory medicine was consulted for a trial of therapeutic plasma exchange (TPE). A central line was placed with the first exchange of 1 plasma volume using 5% albumin replacement fluid (Spectra Optia; Terumo BCT, Lakewood, CO) on hospital day 11 and the second rituximab infusion (cycle 1, week 2) given right after TPE.
Table 2. Lines of Therapy, Organized by Date, With Details of Dosages and Dates
Therapeutic CategoryTherapeutic DetailsDose (if Applicable)Date
SteroidsPrednisone100 mg dailyD36
120 mg dailyD31–35
130 mg dailyD25–30
140 mg dailyD1–8, D19–24
280 mg dailyD13–18
Methylprednisolone1000 mg dailyD9–12
Recombinant erythropoietinDarbepoetin200 μgD2
Intravenous immunoglobulin (IVIG) 1 g/kgD1–2
Rituximab375 mg/mg21000 mgD4
1000 mgD11
1000 mgD18
1000 mgD26
Therapuetic plasma exchange 1 sessionD11
Splenectomy  D33
Figure 1. Hemoglobin trend and number of packed erythrocyte transfusions over the hospital stay. Interventions labeled with rituximab given in 4 doses (days 4, 11, 18, and 26), 1 therapeutic plasma exchange session (day 11), and splenectomy (day 33). The patient was discharged on hospital day 42. Outpatient follow-up hemoglobin numbers shown with disrupted x-axis. Patient was tapered off steroid therapy outpatient on day 96. Blue dots indicate hemoglobin, and red squares indicate the number of transfusions.
Figure 1. Hemoglobin trend and number of packed erythrocyte transfusions over the hospital stay. Interventions labeled with rituximab given in 4 doses (days 4, 11, 18, and 26), 1 therapeutic plasma exchange session (day 11), and splenectomy (day 33). The patient was discharged on hospital day 42. Outpatient follow-up hemoglobin numbers shown with disrupted x-axis. Patient was tapered off steroid therapy outpatient on day 96. Blue dots indicate hemoglobin, and red squares indicate the number of transfusions.
However, on the planned second session of TPE (day 13), the patient developed a fever. He was diagnosed with a catheter-related Enterococcus faecalis bacteremia, treated with ampicillin for 6 weeks, and the central line was removed on day 15. Further TPE sessions were canceled. His steroid regimen was changed to prednisone 2 mg/kg for the following week before return to 1 mg/kg on day 19. Two more rituximab infusions were given on day 18 and day 26. Although the effectiveness of rituximab is expected to manifest within weeks, it can take up to several months in this disease. Because the patient continued to require 2 to 3 red blood cell units daily to hold at a hemoglobin of 4 to 5 g/dL despite these interventions, surgery was consulted. The patient had a laparoscopic splenectomy on day 33 with no perioperative complications. His hemoglobin stabilized at 6 to 7 g/dL afterwards with minimal transfusion requirements. He was discharged 42 days after his initial presentation with close hematology follow-up. Six months after discharge, his hemoglobin recovered to 13 g/dL, and his symptoms resolved completely.

Discussion

This previously healthy patient's grave symptoms and critically low hemoglobin and reticulocytopenia on presentation classified him as having severe wAIHA. A near-zero absolute reticulocyte count as well as the rapid progression to pancytopenia were both predictive of poorer clinical outcomes. Recognition of this hematologic emergency necessitated aggressive treatment beyond initial steroid, immunoglobulin, and recombinant EPO use, which included early initiation of rituximab. First-line use of rituximab was informed by current 2021 expert recommendations (9) and a small randomized controlled trial showing overall response rates of 75% and 31% at 1 year and 63% and 19% at 2 years with and without rituximab use, respectively, with no increase in infectious complications (8).
While simultaneously escalating treatment, we pursued comprehensive diagnostics because of the severity of disease. This included a bone marrow biopsy, normally recommended with disease relapse after steroid therapy (5), to exclude an underlying bone marrow–limited hematologic malignancy that may not have been identified in the previous peripheral blood testing or computed tomography imaging. This also ensured separately that the small paraprotein identified peripherally was consistent with monoclonal gammopathy of undetermined significance.
With no evidence of response to first-line treatment, we—as initially discussed with the patient and confirmed on daily reevaluation—pursued TPE as a category III indication for wAIHA per the American Society of Apheresis guidelines (13). It is category III, given the relatively large volume of distribution of IgG antibodies (unlike largely intravascular IgM) that mediate wAIHA pathophysiology. Unfortunately, our patient had a catheter-associated infection and so we could not complete an empirical trial of at least 2 to 3 sessions of TPE to assess an effect and avoid splenectomy.
There remains little guidance on the optimal timing of splenectomy, with future research needed to identify the patient population with this disease in whom pursuing it earlier may be advantageous. The tripartite risk for postoperative infection, thrombosis, and perioperative mortality have contributed to its deprioritization from a second- to third-line treatment in the 2017 British guidelines (11). However, these concerns predate the modern-day vaccination, thromboprophylaxis, and laparoscopic splenectomy era. Of note, historical data regarding splenectomy are confounded by mixing of primary and secondary wAIHA outcomes, the latter for which splenectomy is less effective. Although splenectomy is currently used in fewer than 10% of patients with wAIHA, it remains the most durable treatment (60–90% response rate, sustained remission 75%) (9, 14, 15).
Our patient ultimately proceeded with laparoscopic splenectomy. Although rituximab could have contributed to improvement, the same-day stabilization of his cell counts within hours of surgery with abrogation of the transfusion requirement show that splenectomy remains integral to the therapeutic armamentarium for severe, relapsing, or refractory wAIHA.

Supplemental Material

Author Disclosures (231141_disclosures.pdf)

References

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Published In

cover image Annals of Internal Medicine: Clinical Cases
Annals of Internal Medicine: Clinical Cases
Volume 3Number 5May 2024

History

Published in issue: May 2024
Published online: 7 May 2024

Keywords

    Authors

    Affiliations

    Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    Yale School of Medicine, New Haven, Connecticut
    Christopher Tormey, MD [email protected]
    Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut
    Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    Funding
    Ms. Waldron is funded by the National Heart, Lung, and Blood Institute (T35HL007649). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Dr. Goshua is funded by the Yale Bunker Endowment and the Frederick A. DeLuca Foundation.
    Disclosures
    Disclosure forms are available with the article online.
    Corresponding Author
    Neeharika Namineni, MD; Department of Internal Medicine, Yale School of Medicine, 20 York Street, New Haven, CT 06510; e-mail, [email protected].

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    Funding Information

    HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI): T35HL007649
    Yale DeLuca Center for Innovation in Hematology Research; Yale Bunker Endowment

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    Neeharika Namineni, Christina Waldron, Christopher Tormey, et al. Severe, Refractory Primary Warm Autoimmune Hemolytic Anemia Requiring 90 Erythrocyte Transfusions. AIM Clinical Cases.2024;3:e231141. [Epub 7 May 2024]. doi:10.7326/aimcc.2023.1141

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