Letters to the Editor Immune thrombocytopenia following vaccination during the COVID-19 pandemic To date, there have been over 3.2 million doses of ChAdOx1 nCoV-19 (ChAd) COVID-19 vaccine (AstraZeneca) and 1 million doses of BNT162b2 (BNT) COVID-19 vaccine (Pfizer-BioNTech) administered in Australia. Among the numerous safety signals that have been raised, we present our case series of immune throm- bocytopenia (ITP) after COVID-19 vaccination.1-4 ITP fol- lowing vaccination has been previously described in other settings and after mRNA-based COVID-19 vac- cines.5-8 A Scottish National Registry study examined general practice data and identified a small increased inci- dence of ITP diagnoses between days 0-27 after vaccina- tion with ChAD.9 We present the clinical characteristics and treatment outcomes of patients diagnosed with ITP following COVID vaccinations (ChAd or BNT) in Australia. After obtaining independent ethics committee approval, we contacted hemostasis hematologists across Australia to participate in our comprehensive survey of clinical presentations of vaccine-associated ITP as defined by the temporal relationship of ITP within 42 days fol- lowing COVID-19 vaccination, without an otherwise apparent alternative cause or thrombosis. Patients with thrombosis or elevated D-dimer levels were investigated and excluded for vaccine-induced immune-mediated thrombotic thrombocytopenia according to international guidelines.10 Response was defined as per international consensus guidelines as a platelet count ≥30x109/L, 2-fold increase over baseline and absence of bleeding. A com- plete response was defined as a platelet count ≥100x109/L and absence of bleeding.11 A total of 14 patients were diagnosed with ITP follow- ing vaccination. Twelve of these cases followed adminis- tration of the ChAd vaccine. Ten cases were de novo ITP, presented in Table 1. Four cases were relapses in patients with previously stable chronic ITP, presented in Table 2. None of the 14 patients had concurrent thrombosis. Among the 12 cases of ITP following administration of the ChAd vaccine, an enzyme-linked immunosorbent Table 1. Demographics and clinical features of patients with newly diagnosed immune thrombocytopenia after COVID-19 vaccination. Age Days COVID-19 Other Platelets at WHO Bleeding First-line Second-line TTR TTCR Platelets Treatments Other and after vaccine antecedent presentation bleeding treatment treatment at day 30 at day 30 relevant gender vaccination vaccinations (and nadir score (x109/L) history (30 days) if later) (x109/L) 52M 27 1st ChAd None 8 1 Petechiae Pred/IVIg None 3 4 176 Pred 5 mg None daily 80F 21 1st ChAd Influenza 0 4 Life - Pred/IVIg Eltrombopag 18 23 157 Pred 75 mg None threatening daily bleeding 82M 3 1st ChAd None 22 (1) 1 Petechiae Pred/IVIg Eltrombopag 10 37 197 Pred 12.5 mg AML in daily remission Eltrombopag (not on chemo) 50 mg daily 60F 3 1st ChAd None 3 1 Petechiae Dex/IVIg Pred 2 3 25 None None 83F 23 1st ChAd None 10 1 Petechiae, Dex/IVIg None 1 3 40 None None ecchymoses (Pulse Dex/IVIg repeated day 21) 61M 22 1st ChAd None 17 0 None Pred/MMF None 2 10 104 Pred 20 mg daily None MMF 500 mg BD 82M 9 1st ChAd None 3 1 Purpura Dex Pred 4 47 8 Dex pulse Influenza repeated vaccination day 17 after presenting with ITP 86M 10 1st ChAd None 5 (3) 3 Major bleeding Pred/IVIg None 6 11 259 Pred 25 mg daily None requiring hospitalization 46M 2 1st BNT None 5 (0) 2 Mild blood Pred/IVIg None 4 7 151 Pred 35 mg daily None loss 22M 6 2nd ChAd 1st ChAd 8 1 Petechiae Pred/IVIg N/A 2 7 N/A N/A AIHA given 4 weeks prior AIHA: autoimmune hemolytic anemia; AML: acute myeloid leukemia; BD: twice daily; BNT: BNT162b2 (Pfizer); ChAd: ChAdOx1 nCoV-19 (AstraZeneca); COVID-19: coronavirus disease 2019; Dex: dexamethasone; F: female; IVIg: intravenous immunoglobulin; ITP: immune thrombocytopenia; M: male; MMF: mycophenolate mofetil; Pred: prednisone; TTCR: time to complete response; TTR: time to response; WHO: World Health Organization. haematologica | 2022; 107(5) 1193 Letters to the Editor Table 2. Demographics and clinical features of patients with relapsed chronic immune thrombocytopenia after COVID-19 vaccination. Age Days COVID-19 Other Chronic Most Platelets WHO Bleeding First- Second- TTR TTCR Platelets Treatments Other and after vaccine antecedent ITP recent at bleeding line line at day 30 at day 30 relevant gender vaccination vaccinations treatments platelets presentation score treatment treatment (x109/L) history prior to (x109/L) vaccination (x109/L) 94F 9 1st BNT None Stable on 86 12 0 None No change None 5 - 73 None None romiplostim to ongoing romiplostim 77M 2 1st ChAd Influenza Stable off 188 6 1 Petechiae Pred/IVIg None 3 8 144 Pred 15 None treatment mg daily 73F 30 1st ChAd None Stable off 255 11 2 Mild blood IVIg None 3 5 215 None None treatment loss 73M 31 1st ChAd None Stable off 120 5 1 Petechiae Pred None 2 4 234 Pred Positive treatment 10 mg DAT and ANA ANA: antinuclear antibodies; BNT: BNT162b2 (Pfizer); ChAd: ChAdOx1 nCoV-19 (AstraZeneca); COVID-19: coronavirus disease 2019; DAT: direct antiglobulin test; Dex: dexamethasone; F: female; IVIg: intravenous immunoglobulin; M: male; Pred: prednisone; TTCR: time to complete response; TTR: time to response; WHO: World Health Organization. assay for platelet factor 4 (PF4) was performed in six and all of these tested negative. The median age of the patients was 75 years (range, 22-94), the median time to presentation after vaccination was 10 days (range, 2-31), and the platelet count at pres- entation was 7x109/L (range, 0-22x109/L). World Health Organization bleeding scores were mild: ten patients had grade 0 or 1, two patients had grade 2, and one patient each had grades 3 and 4.12 Ten cases had no prior history of ITP and all received treatment upfront: seven received prednisone, and three high-dose dexamethasone pulses. Eight patients also received between 1-2 g/kg intravenous immunoglobulins (IVIg) as part of first-line therapy. The median time to response was 3.5 days (range, 1-18). Ten evaluable patients achieved a complete response by a median of 9 days (range, 3-47). Day 30 data were available for nine of these ten patients without a prior history of ITP, as one left Australia: the median platelet count was 151x109/L (range, 8-259x109/L); eight were still on corticosteroids (median prednisone equivalent 20 mg daily), one was on eltrombopag (commenced as second-line treatment) and another was receiving mycophenolate mofetil that had been commenced in first-line treatment in combination with prednisone. One 80-year-old female presented with life-threatening bleeding (influenza vaccination 1 day prior and ChAd 21 days prior to presentation) and after no initial response to escalating prednisone doses and IVIg, eltrombopag was commenced on day 15. Platelets began to respond by day 18, and the platelet count rose to 157x109/L by day 30 after presentation while only on prednisone. One 82-year-old male presented with a platelet count of 3x109/L, and widespread bruising 9 days after his first ChAd vaccination. He was treated with high-dose dex- amethasone and platelets responded, reaching 97x109/L by day 16 (Figure 1A). He received influenza vaccination the following day, but his ITP relapsed by day 32. He responded promptly to a second pulse of high-dose dex- amethasone with a platelet ount of 65x109/L by day 36. He had never previously developed ITP despite numer- ous influenza vaccinations in the past. One 83-year-old female presented with a platelet count of 10x109/L, facial petechiae, and upper chest ecchy- moses 23 days after her first ChAd vaccination (Figure 1B). She responded promptly to a dexamethasone pulse 20 mg daily for 4 days and IVIg infusion 0.4 g/kg for 3 days. She relapsed on day 19 with platelets 23x109/L and new lower limb bruising, and was treated with another pulse of dexamethasone and IVIg 0.4 g/kg for 2 days. In total, there were four patients with chronic ITP who relapsed following COVID-19 vaccination. Three patients receiving ChAd had stable chronic ITP, and were off ITP-directed therapies at the time of COVID-19 vac- cination. They were treated with standard first-line ther- apies and all responded within 3 days. IVIg monotherapy alone was successful in one 72-year- old female with chronic ITP who presented with a platelet count of 11x109/L but responded by day 3, achieving a complete response on day 5; her day 30 platelet count was 215x109/L (Figure 1C), and she had no need for steroids at any time despite having had refracto- ry ITP requiring splenectomy in 1994. Her most recent prior platelet count was 255x109/L less than 3 weeks before vaccination. Her most recent prior ITP treatment had been rituximab monotherapy in 2011. A second chronic ITP patient, a 77-year-old male who received influenza vaccination prior to ChAd vaccination, presented with a platelet count of 2x109/L, achieved a response and complete response by days 3 and 8 respec- tively, had a day 30 platelet count of 144x109/L, and was on a weaning schedule of prednisone at day 30 after ini- tially being treated with prednisone/IVIg upfront. The third patient with chronic ITP, a 73-year-old male with a pre-vaccination platelet count of 120x109/L, was thrombocytopenic (platelet count, 5x109/L) 31 days after ChAd vaccination. He was started on prednisone monotherapy and achieved a response within 2 days, a complete response by day 4, and a platelet count of 234x109/L by day 30 while on prednisone 10 mg daily. The fourth chronic ITP patient in this analysis was a 94-year-old female who received her first dose of BNT 9 days prior to presentation. She had previously enjoyed a stable platelet response on romiplostim for her chronic ITP with a recent platelet count of 86x109/L, falling to 12x109/L without any bleeding; her platelet count returned to baseline within 5 days of presentation. She proceeded to receive her second dose of BNT 21 days 1194 haematologica | 2022; 107(5) Letters to the Editor Figure 1. Clinical course of three separate cases of immune thrombocytopenia following COVID-19 vac- cination. (A) An 82-year-old male with newly diag- nosed immune thomrbocytopenia (ITP) was treated with dexamethasone an initially responded, received influenza vaccination, relapsed, and responded again to another pulse of dexamethasone and wean- ing prednisone taper. (B) An 83-year-old female with newly diagnosed ITP was treated with two pulses of dexamethasone/IVIg. (C) A 73-year-old female had a relapse of chronic ITP after receiving ChAd vaccina- tion, received IVIg 2 g/kg over 2 days as monothera- py. ChAd: ChAdOx1 nCoV-19 (AstraZeneca); IVIg: intravenous immunoglobulin. A B C after the first, relapsing again on day 15 with a platelet count of 14x109/L before returning to her stable baseline within a further 7 days. Our case series of vaccine-associated ITP comprises more cases of ITP following administration of the ChAd vaccine than after the BNT vaccine (12 from 3.2 million ChAd vaccinations vs. 2 from 1 million BNT), although there may be an ascertainment bias due to greater scruti- ny of patients following ChAd vaccination, as suggested in a recent Scottish study even though this paper also concluded that there was an increased rate of ITP diag- noses of 1.13 per 100,000 doses.9 In contrast, a Scandinavian epidemiological study was unable to iden- tify an increased rate of ITP diagnoses although rates of “unspecified thrombocytopenia” and bleeding events were increased significantly.13 Our study was not designed to address the questions of frequency or causal- ity. Our designation of these cases as “vaccine-associat- ed” ITP as opposed to co-incident ITP is based on the clinical diagnosis of ITP as one of exclusion. As vaccine association cannot be excluded, we cannot conclude that these patients have primary ITP, conceding that future outcomes may eventually justify revision of our diagno- sis, which is common in ITP.14 Two of 14 cases are confounded at presentation by the recent administration of influenza vaccination, and another patient received influenza vaccination shortly after initial recovery from ITP before relapsing. However, these limitations reflect an unavoidable real-world dilem- ma as public health imperatives to protect populations at risk during a pandemic will likely outweigh the consider- ably smaller numerical risk of uncertain outcomes and vaccination side effects when immunization programs overlap. Most cases responded rapidly to first-line therapy although the majority remained on corticosteroids for at least 30 days (median prednisone equivalent dose 13.75 mg daily for all cases, 20 mg daily for those with newly diagnosed ITP). Patients whose chronic ITP relapsed after vaccination responded rapidly to first-line therapies, con- sistent with other observations,8 and reassuringly for those with underlying ITP who are at present hesitant to receive COVID-19 vaccination. So far, in three patients, a single pulse of high-dose dexamethasone was insufficient to maintain remission in this cohort, but repeat courses have been successful and well tolerated. Additional haematologica | 2022; 107(5) 1195 Letters to the Editor strategies used successfully include eltrombopag and mycophenolate mofetil. Further data will be needed to understand the durability of these responses. We anticipate that there may be cases along a spectrum of clinical presentations between vaccine-induced immune-mediated thrombotic thrombocytopenia and vaccine-associated ITP, as have already been noted else- where.15 In our cohort, overlapping characteristics have not yet been identified, and all six patients with samples tested were negative for anti-PF4 antibodies. Both local and international registries are currently col- lecting data that will be useful for investigating treatment strategies and clinical outcomes for patients developing ITP following COVID-19 vaccination. Philip Young-Ill Choi,1,2 Danny Hsu,3 Huyen Anh Tran,4 Chee Wee Tan,5 Anoop Enjeti,6 Vivien Mun Yee Chen,7,8 Beng Hock Chong,9 Jennifer Curnow,10 Dominic Pepperell11 and Robert Bird12 1The Canberra Hospital, Canberra, Australian Capital Territory; 2John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory; 3Liverpool Hospital, Liverpool, New South Wales; 4The Alfred Hospital, Melbourne, Victoria; 5Royal Adelaide Hospital, Adelaide, South Australia; 6Calvary Mater Hospital, Newcastle, New South Wales; 7ANZAC Research Institute, University of Sydney, Sydney, New South Wales; 8Department of Haematology, Concord Repatriation and General Hospital, Sydney, New South Wales; 9NSW Health Pathology, St George Hospital, University NSW, Sydney, New South Wales; 10Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales; 11Fiona Stanley Hospital, Perth, Western Australia and 12Princess Alexandra Hospital, Brisbane, Queensland, Australia Correspondence: PHILIP YOUNG-ILL CHOI - phil.choi@act.gov.au doi:10.3324/haematol.2021.279442 Received: June 15, 2021. 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