TABLE 1.
Characteristics of patients with new‐onset development of autoimmune hemolytic anemia (AIHA) following COVID‐19 vaccination
| Country (case no.) | Type of AIHA | Gender‐age, years | Vaccine name (vaccine type) | Onset time of symptoms‐primary clinical symptoms | Hematologic test results | Other tests | Medication and outcome | Reference |
|---|---|---|---|---|---|---|---|---|
| India (1) a | Warm AIHA | M‐71 | Oxford/AstraZeneca |
‐ 30 days after first dose. ‐ Fatigue, Hb: 5 mg/dl |
‐ Normocytic normochromic anemia with RBC agglutination, polychromasia, nucleated RBC, spherocytosis. ‐ High reticulocyte count (6.6%) low haptoglobin level. ‐ MCV 85 fl, MCH 31 pg, MCHC 37 g/dl, platelet count 2.83 lakhs. ‐ DAT: anti‐RBC IgG showed 4+ reaction. |
‐ Unconjugated hyperbilirubinemia with raised LDH. ‐ Transferrin saturation: 108.38%, Ferritin level: 2238.7 ng/ml. Vitamin B12 and folic acid levels were normal. ‐ Bone marrow: hypercellular with erythroid hyperplasia. |
‐ Treatment was done with high dose IVIG. ‐ Blood transfusion was done whenever Hb dropped <5 mg/dl. ‐ Hb improved by 2 weeks and there was no need to blood transfusion after 12 days of IVIG. |
12 |
| USA (2) b | Warm AIHA | F‐66 | Moderna mRNA vaccine |
‐ 4 months after second dose. ‐ Hb: 9.9 mg/dl; Hct: 29.4%. |
‐ High reticulocyte count, moderate number of spherocytes. ‐ DAT: anti‐RBC IgG showed 4+ reaction (without C3). |
‐ Total bilirubin: 2.5 mg/dl; direct bilirubin: 0.7 mg/dl. ‐ High serum LDH, and low serum haptoglobin level. ‐ Physical examination: slight uvular icterus. |
‐ Treatment was done by prednisone. ‐ Hgb/Hct began to be normalized within 2 weeks of treatment. |
13 |
| Portugal (3) | Warm AIHA | F‐88 | COVID‐19 mRNA vaccine |
‐ 2 days after second dose. ‐ Asthenia, jaundice. |
‐ Normocytic normochromic anemia ‐ Hb: 4.5 mg/dl, hematocrit: 13.8%, normal mean globular volume, normal mean globular hemoglobin concentration, normal proportion of reticulocytes, normal platelet counts. ‐ DAT: High titers of anti‐RBC IgG and high anti‐C3d titers. No cold agglutinins were detected. |
‐ High LDH, total bilirubin and indirect bilirubin, AST levels, normal ALT level, low haptoglobin level. ‐ Acute kidney injury with a high creatinine and urea with mild compensated metabolic acidosis. ‐ Urinalysis: hemoglobinuria without bilirubinuria. |
‐ Treatment was done using transfusion with erythrocyte concentrate. ‐ Methylprednisolone therapy results in stabilization of Hb level and decreased bilirubin. ‐ On the fifth day, reticulosis was 9.3% and kidney injury improved. ‐ From the sixth day, normalization of Hb and hematocrit was begun. The corticosteroid therapy was switched to oral. ‐ On the 11th day patient was asymptomatic with a Hb of 7.2 g/dl. |
14 |
| Switzerland (4) | Warm AIHA | M‐77 | Moderna mRNA‐1273 |
‐ 5 days after first dose. ‐ Weakness, fatigue and shortness of breath. |
Normochromic normocytic anemia with increased reticulocytes mild leukocytosis. DAT: Warm AIHA was diagnosed. |
‐ High transaminases, LDH and bilirubin and low haptoglobin. ‐ Abdominal ultrasound: discrete inhomogeneous liver parenchyma. ‐ Anti‐MPO, p‐ANCA, c‐ANCA antibodies were normal. |
‐ Treatment was done using prednisone. ‐ Two weeks later, Hb level increased to 112 g/L, reticulocytes, bilirubin, and LDH levels also decreased. ‐ Prednisone gradually tapered and the Hb level was almost normalized after 10 weeks. |
15 |
| USA (5) c | Warm AIHA | M‐84 | Pfizer‐BioNTech |
‐ 19 days after first dose. ‐ Increased urinary frequency and dizziness. ‐ Urine culture was positive for Enterobacter cloacae. |
‐ Patient's chronic anemia was worsened. ‐ Hb: 8.8 g/dl and more reduced later, high MCV 107, elevated reticulocyte counts. ‐ Leukocytosis, high reticulocyte count, and polychromasia. ‐ Leukoerythroblastic reaction with macrocytic anemia and reticulocytosis, along with moderate neutrophilia and monocytosis. ‐ DAT: Test was positive for anti‐RBC IgG, while was negative for C3. |
LDH was elevated, Haptoglobin was less. |
‐ Treatment was done using Methylprednisolone and prednisone. ‐ Transfusion using packed was also done. ‐ Hb level increased to 7.7 g/dl on the second day of hospitalization and remained stable at discharge on the third hospital day as well as during the follow‐up. ‐ Hb reached to 9.0 g/dl 1 week after the discharge. |
16 |
| USA (6) | Mixed‐AIHA | F‐41 | Moderna mRNA‐1273 |
‐ 7 days after first dose. ‐ Fatigue, dark urine, dyspnea. |
‐ Hb: 7.1 g/dl, low MCV, high reticulocyte count. ‐ Mixed warm/cold AIHA was observed. ‐ Warm autoantibody consisted with the presence of either IgG4 or IgG3. |
‐ H levels of total and direct bilirubin ‐ Bilirubin, low haptoglobin, high LDH. |
‐ Transfusion using packed was also done. ‐ Various types of symptoms and hematological complications was observed. ‐ Treatment was continued using prednisone, mycophenolate mofetil, IVIG and rituximab up to 80 days after vaccination to manage her complications. |
17 |
| Japan (7) d | Warm AIHA | F‐75 | Pfizer‐BioNTech |
‐ 14 days after first dose. ‐Anemia |
Direct and indirect coombs tests: positive hemolytic anemia | Elevation of serum LDH and indirect bilirubin levels. | Oral prednisolone therapy was done. The anemia improved soon after the treatment. | 18 |
| Saudi Arabia (8) | Cold AIHA | F‐45 | Pfizer‐BioNTech |
‐ 3 days after first dose. ‐ Shortness of breath, palpitations, fatigue and dark urine. |
‐ Hb: 57 g/L, 10% reticulocytes. ‐ Peripheral blood film: marked agglutination. ‐ DAT: test was positive for C3. |
‐ Physical examination: Tachycardia, jaundice and pallor. ‐High LDH level, high total bilirubin, and direct bilirubin. |
‐ Transfusion was also done. ‐ The patient was also treated with rituximab. ‐Complete remission was achieved 8 weeks after rituximab therapy. |
19 |
| USA (9) e | Warm AIHA | F‐42 | Moderna |
‐ 7 days after first dose. ‐ Dizziness and light headedness, breath shortness with activity, palpitations, blurred vision, weakness, and fatigue. |
‐ Hb: 4.5 g/dl, MCV: 90 fl, absolute reticulocyte count: 19.9 × 109/L. ‐ A peripheral blood smear: A few schistocytes, polychromasia, and anisocytosis. ‐ DAT: test was positive for IgG and C3 with identification of warm autoantibodies. |
‐ High LDH level and low haptoglobin level. ‐ Mildly elevated indirect bilirubin. Creatinine was normal range ‐ Normal serum iron and iron saturation but mildly elevated ferritin, normal folate and severely low vitamin B12 level. ‐ Anti‐gastric parietal cell IgG and intrinsic factor antibodies were positive. |
‐ Treatment was done using methylprednisolone, and cyanocobalamin. ‐ On 10th day Hb improved and she was discharged. ‐ On the follow‐up hematologic parameters were improved. |
20 |
| Belgium (10) | Warm AIHA | M‐67 | Pfizer‐BioNTech |
‐ 17 days after third dose. ‐Fever, general weakness, fatigue, jaundice, dark urine. |
‐ Hb: 7.5 g/dl, reticulocytopenia, decreased platelet count, ‐ A peripheral blood smear: A few schistocytes, polychromasia, and anisocytosis. ‐ DAT: test was positive for IgG and C3 ‐ DAT: test was positive for IgG and C3 with identification of warm autoantibodies. |
‐ Undetectable level of haptoglobin, high level of LDH and ferritin, total and indirect bilirubin was raised. |
‐ Methylprednisolone was initiated, but in the next morning the Hb level was critically reduced. ‐ Transfusion was delayed as compatible RBC was unavailable. With a delay, compatible RBC was administered. ‐ Methylprednisolone dose was raised due to poor response. On Day 12, a daily plasma exchange was done, as well as weekly rituximab injections. The patient was finally discharged on Day 21, with a steady Hb level of about 7.0 g/dl. |
21 |
| Japan (11) f | Warm AIHA | F‐53 | Pfizer‐BioNTech |
‐ 14 days after second dose. ‐ Yellow skin and conjunctiva and anemic palpebral. |
‐ Hb: 6.9 g/dl. ‐ Low platelet count. ‐ Erythroid hyperplasia with megaloblastic alterations on the smear of bone marrow. ‐ Both direct and indirect coombs tests were positive. ‐ Cold agglutinin level was low. |
‐ High indirect bilirubin, elevated LDH, low haptoglobin, positive lupus coagulant and anti‐nuclear antibody. | ‐ Treatment with prednisolone together with once RBC transfusion gradually improved the symptoms. | 22 |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DAT, direct antiglobulin test; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MPO, myeloperoxidase.
The patient had a history of COVID‐19 infection around 6 months before vaccination.
The patient had long‐term psoriatic arthritis on adalimumab therapy for >5 years. Her Hgb/Hct, platelet and WBC counts were normal 4 months earlier.
The patient had a history of malignancies, cardiovascular and digestive disorders with mild chronic anemia 4 months before presentation.
The patient had history of chemotherapy for lung cancer and a history of H. pylori eradication for idiopathic thrombocytopenic purpura (ITP).
The patient had a history of hypertension, congenitally mute and deaf, iron deficiency anemia, and provoked venous sinus thrombosis treated with anticoagulation.
The patients displayed coexistence of AIHA and immune thrombocytopenia (Evans syndrome) associated with the systemic lupus erythematosus.