key: cord-0991256-vmbkto6j
authors: Lee, Eun-Ju; Beltrami-Moreira, Marina; Al-Samkari, Hanny; Cuker, Adam; DiRaimo, Jennifer; Gernsheimer, Terry; Kruse, Alexandra; Kessler, Craig; Kruse, Caroline; Leavitt, Andrew D.; Lee, Alfred I.; Liebman, Howard A.; Newland, Adrian C.; Ray, Ashley E.; Tarantino, Michael D.; Thachil, Jecko; Kuter, David J.; Cines, Douglas B.; Bussel, James B.
title: SARS-CoV-2 Vaccination and Immune Thrombocytopenia in de novo and pre-existing ITP patients
date: 2021-10-01
journal: Blood
DOI: 10.1182/blood.2021013411
sha: 550cb51b185ab3e0b8d6fb1d5226d00a2f91af0b
doc_id: 991256
cord_uid: vmbkto6j

Cases of de novo immune thrombocytopenia (ITP) – including a fatality – following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in pre-existing ITP. In this study, four data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a ten-center retrospective study of adults with pre-existing ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA, United States) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1—9] x109/L approximately 1-week post-vaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 109 patients with pre-existing ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30×109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK ITP patients, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in pre-existing ITP or be identified de novo post-SARS-CoV2-vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated.

Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] x10 9 /L approximately 1-week post-vaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 109 patients with pre-existing ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30x10 9 /L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation.

Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK ITP patients, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in pre-existing ITP or be identified de novo post-SARS-CoV2-vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated.

The COVID19 pandemic led to urgent development and widespread use of SARS-CoV-2 vaccines 1,2 . In January 2021, USA Today and the New York Times reported an otherwise-well 56-

year-old physician diagnosed with de novo immune thrombocytopenia (ITP) 3 days after receiving the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine who died 13 days later from intracranial hemorrhage refractory to administered treatments 3, 4 . This widely-publicized case led to interrogating the Vaccine Adverse Events Reporting System (VAERS) for other potential cases of de novo ITP 5, 6 .

Discovery of additional cases of de novo ITP following SARS-CoV-2 vaccination generated considerable concern among patients with pre-existing ITP and their healthcare providers. The desire for potentially life-saving vaccination was tempered by fear of ITP exacerbation and lifethreatening bleeding. This report describes both additional discovery of de novo ITP cases and three independent series each describing outcomes of patients with pre-existing ITP following SARS-CoV-2 vaccination.

VAERS was reviewed to identify potential cases of de novo ITP following SARS-CoV-2 vaccination using search terms: immune thrombocytopenia, thrombocytopenia, decreased platelet count, immunoglobulin (IVIG) therapy, and platelet transfusion (last VAERS access Mar 19, 2021) .

Duplicate entries, reports lacking platelet counts and details of treatments, platelet nadirs >50 6 x10 9 /L, presence of other active conditions including hematologic conditions, IVIG given for other indications, and mislabeled records were excluded. ITP was the presumptive diagnosis in cases of isolated thrombocytopenia <50 x10 9 /L refractory to platelet transfusion in the absence of alternative causes. Eight patients with de novo ITP contacted one author (JBB) and provided additional information; some of these patients may have been entered in VAERS. These patients were included to illustrate management of refractory ITP.

Data for patients with pre-existing ITP were obtained via a ten-center retrospective study of adults with ITP who received a SARS-CoV-2 vaccine between December 2020 and March 2021 and who had a post-vaccination platelet count; all but one center was in the United States. ITP was defined per American Society of Hematology and International Consensus guidelines 7, 8 .

De-identified clinical data were collected from electronic medical records, including patient demographics, duration of ITP, treatment history including past use of rituximab and/or splenectomy, SARS-CoV-2 vaccine type, bleeding symptoms, and platelet counts; all patients with post-vaccination platelet counts were included. The data cut-off for both de novo and existing cases of ITP occurred prior to published reports of vaccine-induced thrombosisthrombocytopenia syndrome (VITT-TTS) 9 following adenoviral vaccines. Therefore testing for anti-platelet factor 4 antibodies had not been performed. The study was approved by the in certain cases, platelet counts were "adequate/normal" and thus could not be used for numerical analyses.

The lowest or highest post-vaccination platelet count was used to characterize post-vaccine change. A 'stable platelet count' was defined as a post-vaccination platelet count within 20% of the pre-vaccination level. An "exacerbation of ITP" was defined as development of any one or more of the following: a) ≥50% decline in platelet count from pre-vaccination baseline; b) >20% decline from pre-vaccination baseline and platelet nadir <30x10 9 /L; and/or c) receipt of rescue therapy for ITP. No distinction was made among patients meeting 1, 2 or 3 criteria for the composite endpoint.

For access to de-identified individual subject data of any of the datasets, please contact eul7001@med.cornell.edu.

A total of 93 records in VAERS included a platelet count, or 'severe' or 'low' platelets and platelet-specific interventions. Of these, 16 were excluded (pre-existing thrombocytopenia (n= 5), pre-existing ITP (n= 10), thrombocytopenia resolved with platelet transfusion only (n= 1)), leaving 77 reports (Table 1 ). All received either the Pfizer BioNTech (BNT162b2) (n=37) or Moderna (mRNA-1273) (n=40) vaccine. The mean age was 63±20 years with 60% female.

Premorbid autoimmune disease was reported in 32%.

Of the 66 reports that specified first or second dose, 51 (77%) developed thrombocytopenia following dose #1 of a SARS-CoV-2 vaccine and 15 (23%) following dose #2. Median platelet count was 3 [1-9]x10 9 /L at a median of 8 [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] days following vaccination (n=73). Seventyfour percent of patients presented with skin or oral mucosa bleeding. Six patients presented with genitourinary (GU) bleeding, 5 gastrointestinal (GI) bleeding and 1 presented with central nervous system (CNS) bleeding. Additional information regarding bleeding was not available; however, the only death noted was the widely-reported "index" patient who developed CNS bleeding. No thrombotic events were reported in these patients.

There was no significant difference in time to symptom onset ( Figure 1 Among 46 records specifying treatment, all patients received IVIG and/or corticosteroids and/or platelet transfusions and 5 received additional agents: thrombopoietin receptor agonists (TPO-RA), rituximab, or vincristine (Table 1 ). An increase in the platelet count to >30x10 9 /L was reported in 26 (93%) of 28 records with a follow-up platelet count. The 2 non-responders included the "index" patient and a 63-year-old man with platelet count of 1x10 9 /L 11 days following Pfizer BioNTech dose #1 with no response to 'typical ITP therapies' by day 4 (outcome unknown).

Additional information was available in 8 patients who contacted one of the authors (JBB) because they were difficult to manage. It is unclear how many of these patients were reported to VAERS. Each case followed dose #1 of the Pfizer-BioNTech or Moderna SARS-CoV-2 vaccine and were distinguished by minimal response to platelet transfusion, corticosteroids, IVIG, and, in 7 of 8, rituximab 5 . Initiation of additional treatment ranged from 3-13 days after diagnosis of ITP. Seven patients received romiplostim (3-7 micrograms/kg) and 1 eltrombopag (75 mg daily).

Other agents included vincristine (1.5 mg IV push) in 6 patients, mycophenolate mofetil, dapsone, and cyclosporine (1 patient each). All 8 patients responded with improvement in platelet count. An 80-year-old woman on warfarin for antiphospholipid syndrome developed subarachnoid and subdural hemorrhages; corticosteroids, IVIG, platelet transfusion, and romiplostim increased her platelet count.

Between December 2020 and March 2021, 117 patients with pre-existing ITP from 10 centers were vaccinated for SARS-CoV-2 and had post-vaccine platelet counts. The mean age was 63 ±17 years, 62% were female, there was a median 12 [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] years since diagnosis of ITP, and patients had received a median of 3 [2] [3] [4] prior medical treatments. Sixty-nine patients were receiving ITP treatment at the time of vaccination, 58 (84%) a TPO-RA. Twenty-seven had undergone splenectomy. Sixteen of 48 off-treatment patients had platelet counts ≥ 150x10 9 /L ( Table 2) .

The median baseline platelet count in 109 patients was 101 [60-199]x10 9 /L assessed 14 days prior to vaccination, and the median platelet count was unchanged at follow-up: 100 [50-195]x10 9 /L at 6 [4] [5] [6] [7] [8] [9] days post-vaccination (Table 3) . Platelet counts rose in 32 (29%), remained stable (within 20% variation from baseline) in 43 (39%), and decreased in 34 patients (31%) (Figure 2A ). Nineteen (17%) developed an exacerbation of ITP (Table 4 ) with 7 patients receiving rescue therapy. Rescue treatments included corticosteroids (n=2), TPO-RA (n=3), IVIG (n=1), and a combination of IVIG, steroids, rituximab and cyclosporine (n=1) as well as increased dosing of ongoing ITP treatment (Supplemental figure S1). All responded to treatment with platelets > 30x10 9 /L or return to pre-vaccination ranges within 2 to 4 weeks without major bleeding (Supplemental Figure S1 ).

The median platelet count prior to the second vaccination was 101 [60 -186]x10 9 /L (n=70) assessed 12 days prior to vaccination. At a median of 5 [3 -8] days post-vaccination the median platelet count was 106 [53-202]x10 9 /L ( Table 3) . Platelets rose in 24 (34%), remained stable in 25 (36%), and declined in 21 (30%) (Figure 2A ). Fourteen (20%) patients developed an exacerbation of ITP. The 9 patients receiving rescue treatment responded with platelets >30x10 9 /L or return to pre-vaccination ranges (Supplemental Figure S1 ).

Patients with prior splenectomy had a significantly higher risk of exacerbation after dose #1 (12/25, 48%) compared to non-splenectomized patients ( Prior use of >5 lines of medical treatment was more common among splenectomized patients (59% vs 11% in non-splenectomized group). The incidence of ITP exacerbation after dose #1 was highest among splenectomized patients with >5 lines of therapy (6/10, 60%) compared to 1/47 (2%) who had not undergone splenectomy and had received ≤4 prior treatments (Table 5 ).

There was no difference in age, gender, vaccine type (data not shown), or history of autoimmune disease (Table 4 ) between those who did and did not develop an ITP exacerbation.

Sixty-three patients had platelet counts available after both doses of a SARS-CoV-2 vaccine. We investigated if the response to dose #1 could predict the effect of dose #2 on platelet count. Of the patients who had stable or increased platelet counts after dose #1, 80% percent had stable or increased counts after dose #2. Among patients whose platelets decreased by > 20% after dose #1, the effect of dose #2 was less consistent: only 44% had again a decrease >20% in platelet counts ( Figure 2B and Supplemental Figure S2 ). Of 5 patients who received rescue treatment following dose #1, 4 did not receive rescue after dose #2.

Of 122 individuals with pre-existing ITP who completed the PDSA survey, 57 received a SARS-CoV-2 vaccine and had post-vaccination platelet counts. The survey did not differentiate between first and second vaccine doses. Forty-four of 57 (75%) respondents were women (mean age 51 years). Vaccine type was Moderna (29), Pfizer-BioNTech (23), Oxford-AstraZeneca (ChAdOx1 nCoV-19) (4), and Janssen (1). Nineteen individuals (33%) reported decreased post-vaccination platelet counts, including 2 with platelets <10x10 9 /L, one with mucocutaneous bleeding (Supplemental Table S1 ). Participants who were post-splenectomy had a higher risk of a post-vaccination platelet decline >100x10 9 /L (RR 1. 8 

Participants in remission had a lower incidence of platelet count decline >100x10 9 /L (RR 0.7 [0.5-0.9]) compared to those with active ITP.

Of 311 participants only 43 (32 female) reported post-vaccination platelet counts of which 11 were higher, 18 were stable and 14 were lower than before vaccination. Vaccine type was Pfizer-BioNTech (24) and Oxford-AstraZeneca (19) . Among the 14 participants reporting decreased platelets, the pre-vaccine median platelet count was 78 [58-173]x10 9 /L falling to 12 

This report describes the effects of SARS-CoV-2 vaccination on platelet counts of patients without known (de novo) and with pre-existing ITP. The study does not include patients with VITT-TTS, nor does it include patients with inherited thrombocytopenia. This is the largest report to date both of patients with apparent de novo ITP identified in VAERS and also of postvaccination platelet counts in patients with pre-existing ITP. We report findings of ITP development or exacerbation secondary to the first large scale administration of mRNA vaccines.

In de novo ITP patients identified from VAERS, the median time to presentation was 8 days, similar to a recent report of thrombocytopenia after the Oxford-AstraZeneca vaccine 10 . While there is evidence dating back to the 1960's, primarily in children, that attenuated live viral vaccines cause ITP perhaps via direct effect on megakaryoctyes 11 . In contrast, the best study of 14 killed vaccines in adults did not identify an increased incidence of ITP post-vaccination, substantial evidence that killed vaccines cause ITP is lacking 12 . While mRNA vaccines are novel, they are thought to represent a new form of "killed" vaccines; there is no reason to suspect they directly impact megakaryocytes. A recent report of a national registry from Scotland suggested that the Pfizer-BioNTech vaccine did not result in an increased incidence of ITP, while results with the Oxford-AstraZeneca vaccine were equivocal 13 . Pre-existing undiagnosed asymptomatic ITP with post-vaccination exacerbation could be one explanation for development of ITP within days post-vaccination. This would also be consistent with the failure to demonstrate an increased post-vaccination incidence of ITP since these cases were evolving at the time of vaccination. Other etiologies for occurrence of de novo ITP include molecular mimicry and underlying predisposition to autoimmunity; these might represent cases not presenting until at least 1 week post-vaccination 14 . No data is available on the etiology or incidence of de novo ITP in this report. This study also did not identify predictive factors for de novo ITP; although, 32% of cases had pre-existing autoimmune disease, which may be higher than expected in the adult US population 15, 16 . Long-term outcomes of post-vaccine cases of ITP could not be assessed.

It is encouraging to note that among VAERS reports with available information, almost 90% of patients responded to first-line ITP treatment: steroids and/or IVIG and/or platelet transfusions.

In 8 patients who were difficult to treat, addition of a TPO-RA and single-dose vincristine led to good responses. Vincristine appeared to accelerate response compared with the expected 7-14 days with TPO-RAs. Reasons not to use anti-CD20 treatment (eg rituximab) for suspected post-vaccination ITP include a 1-8-week time to response, negation of the recent vaccination, and inability to effectively revaccinate for months 17, 18 .

Details regarding the 8 patients unresponsive to first-line therapy were sent to one of the authors featured in a publication of one of these cases in the lay press 19 . As such, these refractory cases likely represent a small fraction of de novo cases of ITP rather than an influx of refractory cases post-vaccination. Exactly why certain de novo cases of ITP, either postvaccination or idiopathic, are refractory is not well understood.

The findings of de novo ITP post-vaccination led to examination of vaccine effects in patients with pre-existing ITP. Surprisingly, post-vaccination changes in platelet counts in this group were approximately evenly divided among those that increased, remained stable, or decreased in all 3 data sources analyzed. We do not have a parallel comparison group for the vaccinated ITP patients, but the post-vaccination platelet fluctuations were prominent in both directions with changes far exceeding those seen in the placebo arms of numerous ITP studies [20] [21] [22] [23] .

In the multicenter cohort of ITP patients, aproximately 1 in 5 developed an ITP exacerbation after vaccination. Rescue treatment -whether increased dosing of ongoing treatment and/or addition of new ITP treatment -was universally effective. No major bleeding occurred.

An increased risk of developing ITP exacerbation in splenectomized patients was independently seen in each of the 3 data sources. Whether having undergone splenectomy, even if successful, represents more refractory ITP or if the absence of the spleen in some way influences (worsens) 16 the vaccination effect on the platelet count is unclear. In the multicenter cohort, a significantly higher proportion of patients developing ITP exacerbation were post-splenectomy, had a longer duration of ITP, and/or had received >5 treatments for ITP. These categories overlap considerably albeit not completely; all suggest that the worse the ITP, the more likely there is to be a thrombocytopenic effect of vaccination. No patient with normal platelet counts offtreatment and who had not undergone splenectomy developed an exacerbation of ITP.

Furthermore, only 1 patient who had a past history of neither splenectomy nor having received >5 treatments had an exacerbation. Thus the patient at greatest risk of a substantial decrease in platelets post-vaccination seems to be one whose treatment history has demonstrated the need for more aggressive ITP therapies.

A critical question was whether platelet response to the first vaccine dose predicted platelet response to the second dose (for 2-dose immunization schedules). Most patients who did not develop ITP exacerbation after the first vaccine dose also did well with the second dose. Over half of those who experienced a decrease in their platelet counts after the first dose had stable or increased platelet counts after the second dose; only 1 patient received ITP-directed therapy after both vaccine doses. This suggests that ITP patients who are eligible to receive additional vaccine doses, especially if they tolerated the first dose well, may safely do so. A decrease in platelet count with a prior vaccine dose does not guarantee the same effect with a subsequent dose. No major bleeding was seen in any patient. Whether this is also the case after booster doses will require further study.

Limitations of this study include its retrospective design and reliance on information of undefined completeness from diverse sources. Since participation in VAERS and the PDSA and UK surveys was voluntary, there might have been an increased number of adverse events and/or poor outcomes driving the choice to report. Since asymptomatic ITP patients may have chosen not to obtain pre-and post-vaccination platelet counts, the exclusion of these patients may have resulted in an over-estimation of platelet decrease post-vaccination. The majority of patients received the Moderna and Pfizer-BioNTech vaccines, limiting ability to assess potential differences in changes with platelet counts following the adenoviral-based Janssen and Oxford-AstraZeneca SARS-CoV-2 vaccines. Incomplete data resulted in different numbers of patients available for different analyses. In a few patients with pre-existing ITP, the pre-vaccination platelet count was obtained months prior to vaccination; however, 75% of pre-vaccination counts were within 1 month of vaccination. Although the timing and number of post-vaccine counts was not fixed, most patients obtained counts 5-7 days after vaccination. As data was de-identified, there may have been overlap between the multicenter and PDSA survey cases.

Despite these limitations, overall there was consistency across each of the 3 ITP cohorts, including similar percentages with increased, stable, and decreased post-vaccination platelet counts as well as the adverse influence of previous splenectomy.

Our data support and expand upon a recent reports of post-vaccination ITP 24, 25 , that the incidence of severe thrombocytopenia and bleeding is low and patients can be managed with standard, and occasionally, intensified approaches to therapy. These data strongly support the safety of the SARS-CoV-2 vaccines, both acutely in the rare patients developing ITP de novo and in patients with pre-existing ITP. Therapy was effective in essentially all who developed clinically-meaningful thrombocytopenia. Obtaining pre-vaccination counts followed by weekly monitoring of the platelet count in consultation with a hematologist after each vaccination may be warranted in most ITP patients, especially those post-splenectomy or who had received 5 or more prior treatment regimens.

In summary, this report provides a factual basis to encourage SARS-CoV-2 vaccination for patients with ITP by describing the relatively infrequent adverse outcomes and their reversibility with treatment. It also encourages receipt of both doses of 2-dose vaccines which appears to be particularly important as SARS-CoV-2 variants emerge. Best known response 30 to 50 x10 9 /L 3 (11.5%) 26 50 to 100 x10 9 /L 7 (26.9%) 100 to 150 x10 9 /L 3 (11.5%) Normalization § 6 (23.1%) Improvement ¶ 7 (26.9%) Time to platelet count >30 x10 9 cells/l < 3 days of treatment 9 (81.8%) 11 SD indicates standard deviation; IQR, interquartile range; IVIG, intravenous immunoglobulin; TPO-RA, thrombopoietin receptor agonist. *More than 1 site of bleeding reported in some cases, excludes one patient with CNS bleeding whose thrombocytopenia resolved with platelet transfusion only and the patient who developed an intracranial hemorrhage 13 after presentation with thrombocytopenia †Includes one person with "anti-thyroglobulin antibody" ‡Antiphospholipid Syndrome in the same patient with other rheumatologic conditions §Platelet count ≥150 x10 9 /l or described as "platelets normalized" ¶No platelet count provided but described as "improved" or "resolved" 

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*Defined as development of any one or more of the following: a) ≥50% decline in platelet count from pre-vaccination baseline; b) > 20% decline from pre-vaccination baseline and platelet nadir < 30x10 9 /L; and/or c) receipt of rescue therapy for ITP. †Prior rituximab use was specifically solicited in the data collection form as opposed to all prior treatment history, which was volunteered by some centers 29 *Defined as development of any one or more of the following: a) ≥50% decline in platelet count from pre-vaccination baseline; b) > 20% decline from pre-vaccination baseline and platelet nadir < 30x10 9 /L; and/or c) receipt of rescue therapy for ITP.