A 15-year-old Chinese girl, with repeated skin petechiae and ecchymosis for more than one year and three months, was admitted to our hospital with symptoms worsen for one week in January 2021. On August 30,2019, she presented to local hospital in view of petechiae seen on the trunk after upper respiratory tract infection. Blood routine showed purely severe thrombocytopenia (2×109/L) and clinical biochemistry examinations were normal. Bone marrow smear and flow cytometry identified immune thrombocytopenia purpura (ITP). According to the latest diagnostic criteria and treatment strategy for ITP[4, 5]. She was treated with high-dose dexamethasone (40mg per day) for 4 days. Following this, she got a transient, slightly increase in platelet to 32×109/L.
On September 14,2019, she experienced a flare onset and went to a Hematology Specialist Hospital. Blood count manifested mild anemia (hemoglobin = 114g/L) and thrombocytopenia (7×109/L). She underwent bone marrow biopsy, which showed megakaryocytic hyperplasia with immaturity with no significant dysplasia or increased blasts, with no evidence of metastatic carcinoma, lymphoma or granulomas. Myelodysplastic Syndrome-Associated exome sequencing analysis did not identify a pathogenic causative mutation. Flow cytometry showed no evidence of lymphoproliferative disorder or myeloid neoplasm. The patient also underwent tests for secondary thrombocytopenia and was found to have negative results for antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antigen, anticardiolipin antibody and lupus anticoagulant. Viral infections known to trigger ITP (Epstein–Barr virus [EBV], seasonal influenza, adenovirus, hepatitis C, hepatitis B, human immunodeficiency virus, Varicella Zoster virus, and cytomegalovirus [CMV]) were excluded with serologic tests. The history and investigations were consistent with a diagnosis of ITP. A platelet count showed no improvement after given high-dose dexamethasone(HD-DXM) again. Therapy with recombinant human thrombopoietin (rhTPO) of eleven days resulted in platelet count rapidly recovery (209×109/L). She was discharged and maintenance therapy with Chinese herbal medicine, providing an ongoing remission of 9 months.
On July 10, 2020, she presented with epistaxis, melena, petechiae, bruises, hematuria and uterine bleeding again after urinary tract infection. Laboratory findings revealed very severe thrombocytopenia (0×109/L) and moderate-to-severe anemia (53g/L ~ 90g/L) with normal white blood cell and coagulation. Coombs’ test was positive. A diagnosis of Evans’ syndrome was made. From then on, she had endured numerous flares, all of which required necessitated multiagent treatment. She experienced several severe flares over the next 5 months and failing to respond to multiagent therapy including Methylprednisolone 180mg twice daily for three days then 40mg per day, TPO 15000 unit per day, initially Eltrombopag 25mg per day for 8 days then 75mg per day over 2 months, 1 g/kg of intravenous immunoglobulin (IVIG) over 2 days, another round of HD-DXM, 2 doses of Rituximab (300mg/dose/week), Cyclosporine 125mg twice daily (4.0mg/kg) and azathioprine 50mg per day (Fig. 1).
In November 2020, the patient developed hemolysis and persistent hematuria and uterine bleeding with headache, and performed a cerebral computed tomography (CT) scan showing a little subarachnoid hemorrhage. Fundoscopy exhibited mottled hemorrhage around the optic disc of the left eye and massive hemorrhage under the internal limiting membrane in the macular region. Symptoms continued to worsen and Doppler ultrasound of left eye showed vitreous hemorrhage resulting in left eye blindness finally. Multiagent therapy and platelets and erythrocytes transfusion were given. She had a transient improvement in bleeding tendency but persistent thrombocytopenia.
On January 2, 2021, the patient's bleeding and hemolytic symptoms further aggravated, so she was transferred to our hospital. On admission, physical examination showed that she was severe anemia, moderate scleral jaundice, systemic edema and bleeding. She was repeatedly conducted flowcytometric surveillance for malignancy, autoimmune lymphoproliferative syndrome and PNH, as well as repeated bone marrow testing still manifesting megakaryocytic hyperplasia with immaturity. Genetic testing for inherited blood disorders was negative. Hematology investigations showed a positive Coombs’ test for AIHA with C3d antibodies (direct antiglobulin testing positive and indirect antiglobulin testing weakly positive). Antiplatelet antibodies to glycoproteins GPIIb/IIIa, GPIb/IX, and GPIa/IIa showed positive GPIIb/IIIa in circulating plasma. Her symptoms and examinations were still consistent with a diagnosis of ES. She was given multiagent therapy including HD-DXM, rhTPO, Avatrombopag, Eltrombopag, 0.4g/kg of IVIG over 5 days, Splenectomy and Sirolimus. During this period, the patient suffered from severe bleeding with aggravation of hemolysis for many times, and it improved after active blood transfusion, anti-infection and anti-hemolysis treatment, and the platelets did not rebound significantly. She had poor responses to above different therapeutic interventions(Fig. 2). On March 15, 2021, she was administered orally Zanubrutinib 160 mg twice a day. After 8 weeks, she experienced a dramatic clinical response with immediate improvement of platelet (48×109/L), and hemoglobin returned to normal. After 6 months, she achieved platelet count greater than 100×109/L. Then zanubrutinib was gradually tapered and discontinued due to hair loss and economic factors, but still providing an ongoing remission of 8 months so far. There were no obvious adverse events during the application.