Dear Editor,
Among various medical conditions associated with COVID-19 vaccination, thrombocytopenia is a rare but important hematologic condition, which can be associated with severe hemorrhagic or thromboembolic complications [1, 2].
A 66-year-old woman presented with malaise, lymphadenopathy, oral bleeding, and purpura 2 days after receiving the first dose of the BNT162b2 vaccine (Pfizer-BioNTech). The patient had no medical history of thrombocytopenia. A blood test performed 2 years ago revealed a normal platelet count. The patient was febrile and generally ill with bleeding symptoms such as purpura and hematuria. Multiple soft and non-tender enlarged lymph nodes were observed in the bilateral neck and axilla. Blood tests showed severe thrombocytopenia (< 1 × 109/L) with undetectable levels of immature platelet fraction (IPF) and mild normocytic anemia (hemoglobin, 11.6 g/dL). Although the white blood cell count (5.7 × 109/L) was normal, the lymphocyte count was slightly decreased (12.9%; 75.4% neutrophils and 7.5% monocytes). Coagulation tests showed normal results except for a slight increase of fibrin degradation product level. Serum anti-platelet factor 4 (PF4) antibodies were not detected. Biochemical analysis showed mildly elevated levels of lactate dehydrogenase (390 U/L) and inflammatory markers (C-reactive protein [2.6 mg/dL] and ferritin [182 ng/mL]). The levels of soluble interleukin-2 receptor (sIL-2R, 3283 U/mL) and platelet-associated IgG (PAIgG, 6280 ng/107 cells) were highly elevated. Computed tomography (CT) showed right pulmonary basilar consolidation, mild hepatosplenomegaly, and systemic lymphadenopathy, without brain infarctions or hemorrhages. The PCR test for SARS-CoV-2 using nasopharyngeal swabs showed negative results.
Platelet transfusion did not ameliorate the thrombocytopenia. Bone marrow examination revealed hypercellular marrow with markedly increased megakaryocytes, suggesting immune thrombocytopenia (ITP). Neither prednisolone (1 mg/kg/day) and intravenous immunoglobulin (IVIG) treatment nor subsequent treatment with pulsed methylprednisolone (500 mg/day; 3 days), romiplostim, and danazol improved her platelet count (Fig. 1). Blood samples collected on the fifth day of admission showed anti-platelet glycoprotein IIb/IIIa antibodies, which confirm a diagnosis of ITP. Slow vincristine infusion (0.04 mg/kg; 8 h) on the seventh day slightly increased her platelet count with marked elevation of IPF. Thereafter, her platelet count, and the associated symptoms gradually improved. On the 13th day, CT showed resolution of the lung consolidation, lymphadenopathy, and splenomegaly. On the 22nd day, she was discharged without any sequelae.
Thrombocytopenia after COVID-19 vaccination accompanied by thrombosis is usually reported as thrombosis with thrombocytopenia syndrome or vaccine-induced immune thrombotic thrombocytopenia [3], which is associated with anti-PF4 antibodies and usually develops after inoculation with adenoviral vector-based vaccines. Further, ITP after COVID-19 vaccination usually presents with severe thrombocytopenia and hemorrhagic symptoms [1, 4,5,6,7]. The present case was considered vaccine-associated ITP, established by the presence of serum anti-glycoprotein IIb/IIIa antibody, one of the platelet autoantibodies [8]. These were speculated to be present before vaccination, suggesting the existence of subclinical ITP prior to vaccination. Thus, COVID-19 vaccination may aggravate thrombocytopenia in patients with unrecognized subclinical ITP.
Although most cases of COVID-19 vaccine-related ITP were responsive to initial treatment with steroids and/or IVIG [1, 4,5,6,7], some patients died of intracranial hemorrhage according to reports from the Vaccine Adverse Event Reporting System [9]. Although the present case showed a very high risk of life-threatening hemorrhage, vincristine yielded a rapid response. It is reported that a slow infusion of vincristine can inhibit macrophage function and platelet phagocytosis in ITP [10]. We selected vincristine treatment based on the following reasons: (i) the increased PAIgG levels imply the existence of well-opsonized platelets, resulting in efficient vincristine uptake by the macrophages through phagocytosis, and (ii) the elevated sIL-2R levels indicated macrophage activation-associated hypercytokinemia, which may present with systemic lymphadenopathy and hepatosplenomegaly. It might be that mRNA COVID-19 vaccines stimulate macrophage activity, which in turn might be especially sensitive to vincristine.
In summary, we describe a case of severe and refractory ITP associated with COVID-19 vaccination, which ameliorated rapidly after vincristine treatment. COVID-19 vaccination could cause the sudden development of severe ITP even in previously healthy patients, in whom platelet autoantibody could be present. Although further studies are required to establish a standard therapy for COVID-19 vaccine-associated ITP, vincristine could be considered a treatment option for refractory ITP, especially in patients with clinical findings suggestive of hypercytokinemia and macrophage activation.
References
Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, Semple JW, Arnold DM, Godeau B, Lambert MP, Bussel JB (2021) Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol 96(5):534–537. https://doi.org/10.1002/ajh.26132
Simpson CR, Shi T, Vasileiou E, Katikireddi SV, Kerr S, Moore E, McCowan C, Agrawal U, Shah SA, Ritchie LD, Murray J, Pan J, Bradley DT, Stock SJ, Wood R, Chuter A, Beggs J, Stagg HR, Joy M, Tsang RSM, de Lusignan S, Hobbs R, Lyons RA, Torabi F, Bedston S, O’Leary M, Akbari A, McMenamin J, Robertson C, Sheikh A (2021) First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nat Med 27(7):1290–1297. https://doi.org/10.1038/s41591-021-01408-4
Bussel JB, Cines DB, Dunbar CE, Michaelis LC, Kreuziger LB, Lee AYY, Pabinger-Fasching I (2021) Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced thrombotic thrombocytopenia). https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia. Accessed 30 Sept 2021
Shah SRA, Dolkar S, Mathew J, Vishnu P (2021) COVID-19 vaccination associated severe immune thrombocytopenia. Exp Hematol Oncol 10(1):42. https://doi.org/10.1186/s40164-021-00235-0
Helms JM, Ansteatt KT, Roberts JC, Kamatam S, Foong KS, Labayog JS, Tarantino MD (2021) Severe, refractory immune thrombocytopenia occurring after SARS-CoV-2 vaccine. J Blood Med 12:221–224. https://doi.org/10.2147/JBM.S307047
Idogun PO, Ward MC, Teklie Y, Wiese-Rometsch W, Baker J (2021) Newly diagnosed idiopathic thrombocytopenia ost COVID-19 vaccine administration. Cureus 13(5):e14853. https://doi.org/10.7759/cureus.14853
Candelli M, Rossi E, Valletta F, De Stefano V, Franceschi F (2021) Immune thrombocytopenic purpura after SARS-CoV-2 vaccine. Br J Haematol. https://doi.org/10.1111/bjh.17508
Al-Samkari H, Rosovsky RP, Karp Leaf RS, Smith DB, Goodarzi K, Fogerty AE, Sykes DB, Kuter DJ (2020) A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood Adv 4(1):9–18. https://doi.org/10.1182/bloodadvances.2019000868
Welsh KJ, Baumblatt J, Chege W, Goud R, Nair N (2021) Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine 39(25):3329–3332. https://doi.org/10.1016/j.vaccine.2021.04.054
Ahn YS, Harrington WJ, Mylvaganam R, Allen LM, Pall LM (1984) Slow infusion of vinca alkaloids in the treatment of idiopathic thrombocytopenic purpura. Ann Intern Med 100(2):192–196. https://doi.org/10.7326/0003-4819-100-2-192
Acknowledgements
We thank Mr. Akihisa Kamiryo and Ms. Aya Tanaka (Japanese Red Cross Tohoku Block Blood Center) for providing excellent technical supports.
Author information
Authors and Affiliations
Contributions
K.S. designed the research, analyzed and interpreted the data, and wrote the paper. S.I. analyzed and interpreted the data, and wrote and organized the paper. S.H. and Y.K. analyzed and interpreted the data. H.H. and T.I. analyzed and interpreted the data and supervised the paper. All authors approved the final manuscript.
Corresponding author
Ethics declarations
Ethical approval
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 and its later amendments.
Informed consent
Informed consent was obtained from the patient for being included in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Saito, K., Ichikawa, S., Hatta, S. et al. Vincristine therapy for severe and refractory immune thrombocytopenia following COVID-19 vaccination. Ann Hematol 101, 885–887 (2022). https://doi.org/10.1007/s00277-021-04666-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-021-04666-x