key: cord-0715889-dj1qskmq
authors: Woolley, Philippa; Tailor, Anish; Shah, Raakhee; Westwood, John‐Paul; Scully, Marie
title: Real‐world, single‐center experience of SARS‐CoV‐2 vaccination in immune thrombocytopenia
date: 2022-04-05
journal: J Thromb Haemost
DOI: 10.1111/jth.15704
sha: bcc04f56cc2868110a97ce6f70e4f71c3416851d
doc_id: 715889
cord_uid: dj1qskmq

BACKGROUND: Immune thrombocytopenic purpura (ITP) relapse following vaccination remains poorly reported in the adult population. OBJECTIVES: This report details real world data from the largest single‐center cohort of ITP relapse following severe acute respiratory syndrome (SARS‐CoV‐2) vaccination. METHODS: The vaccination status of 294 patients under active follow‐up was reviewed. A total of 17 patients were identified resulting in an incidence of ITP relapse following SARS‐CoV‐2 vaccination in this cohort of 6.6% and an incidence of newly diagnosed ITP following SARS‐CoV‐2 vaccination of 1.4%. RESULTS: Patients were noted to develop marked deviation of platelet count from baseline following vaccination (P =< .0001). Fourteen patients had a prior diagnosis of ITP and median follow‐up following diagnosis was 4 years (range 0–45 years). Days from vaccination to presentation ranged from 2–42 (median 14) and the follow‐up period was 34 weeks. Fifteen patients (88%) presented with symptoms and all 17 patients developed symptoms during the follow‐up period. Nine patients (53%) received a second dose of vaccine during the follow‐up period with seven patients (78%) requiring therapeutic support to facilitate second vaccination. Decision to treat patients was multi‐factorial and aimed at decreasing bleeding symptoms and obtaining a platelet count >30 × 10(9)/L. Sixteen patients (94%) required therapeutic intervention and at the end of the follow‐up period, four patients (24%) remained unresponsive to treatment with a platelet count <30 × 10(9)/L. CONCLUSION: Vaccination of ITP patients continues to have important clinical benefit; however, recommendations for patients who relapse remain lacking. This report outlines the real‐world patient outcomes in the era of widespread SARS‐CoV‐2 vaccination.

Severe acute respiratory syndrome (SARS-CoV-2) was declared a global pandemic in 2019. The disease syndrome associated with the virus has been linked with significant morbidity and mortality. 1, 2 As of June 2021, there have been 3.92 million deaths worldwide and more than 181 million recorded cases. 3 Vaccination remains the current most important factor available to change the course of this pandemic and decrease morbidity and mortality.

Vaccines licensed at an unprecedented rate have enabled widespread roll-out of effective protection against the severe effects of SARS-CoV-2. [4] [5] [6] Highlighting unexpected outcomes of widespread vaccination within certain patient groups aims to decrease adverse events associated with vaccines within the population 7 and improve patient outcomes.

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by isolated thrombocytopenia (platelet count <100 × 10 9 /L) 8 and a hallmark of the condition is no clinical or laboratory features to suggest another underlying or secondary cause. 9, 10 Patients with ITP are at higher risk of bleeding events at lower platelet counts and treatment is aimed at decreasing bleeding complications, improving quality of life and decreasing treatment side effects. 11 Thrombocytopenia in COVID- 19 infection remains rare (5% in hospitalized patients and 8% in intensive care patients in initial reports of the pandemic) 12 and thrombosis remains an overwhelming hematological feature of the disease course with considerable associated morbidity and mortality. 13 We report the largest single-center cohort in the United (AstraZeneca) vaccine and cases diagnosed with vaccine induced thrombocytopenia and thrombosis (VITT) were excluded. ITP diagnosis was confirmed as per the international consensus guidelines 10 and the American Society of Hematology guidelines. 15 Full blood count analysis was performed on a SYSMEX XN-1000 hematology analyzer (Sysmex Corporation) and all samples were analyzed within 2 h of being taken. Immature platelet fraction (IPF) was analyzed in conjunction with the platelet count for each sample with normal range being between 1% and 5%. Patients attended for blood counts as clinically indicated during the follow-up period.

Treatment responses were analyzed and response to treatment was categorized into three groups as per previously defined categories: 16 complete response (CR)-platelet count rise >100 × 10 9 /L; partial response (PR)-platelet count rise >30 × 10 9 /L and <100 × 10 9 /L; or no response (NR)-platelet count <30 × 10 9 /L. Patients' presenting symptoms were classified (as per previously recognized bleeding score) 17 into three groups (asymptomatic, cutaneous bruising, bleeding [petechiae/mucosal]) and documented during clinical consultations. Mucosal bleeding was further characterized into site (oral mucosal, gastrointestinal, or menorrhagia).

Decision to treat was based on established guidelines, specific guidelines, 18 and clinical expertise.

Statistical analysis was performed using GraphPad PRISM version 9 (GraphPad Software). Parametric paired and non-paired ttests were used to compare groups. An alpha value of <0.01 was considered statistically significant. of the 17 patients developed relapse of ITP (incidence of 6.6%) and 3 patients presented as newly diagnosed ITP (incidence of 1.4%; Figure 1 ).

The 17 patients with laboratory or clinical features of relapse following COVID-19 vaccination, median age for the cohort was 53 years (range; . Eight patients (47%) were male, and 9 patients (53%) were female. Years since diagnosis of ITP ranged 

Patients were offered vaccination as per the National Health Service vaccination priority schedule and vaccine availability. Table 1 summarizes the key features of the cohort.

F I G U R E 1 Distribution of vaccines and outcomes of the cohort during follow-up period. ITP, immune thrombocytopenic purpura

All patients developed either bleeding symptoms or confirmed new onset thrombocytopenia following vaccination, with no other precipitating cause. Days from vaccine to presentation ranged from 2-42 (median 15). Baseline platelet count for the cohort prior to vaccination count ranged from 30 × 10 9 /L -312 × 10 9 /L (median 129 × 10 9 /L). Of the 14 patients with historical counts, 9 (53%) were in CR, 5 (47%) were in PR, and no patients had platelet count <30 × 10 9 /L. Immature platelet fraction (IPF) was inversely proportional to nadir platelet count (P = .009) and ranged from 13.5%-44.5%

(median 27.2%). Platelet nadir for the cohort following vaccination ranged from 0 × 10 9 /L to 42 × 10 9 /(median 6 × 10 9 /L) with 16 of the 17 patients (94%) developing a platelet nadir <30 × 10 × 10 9 /L. At the end of the follow-up period, the current platelet count for the cohort was a median 104 × 10 9 /L (range 4 × 10 9 /L−300 × 10 9 /L) and 10 patients (59%) achieved a CR. Four patients (24%) remained unresponsive to therapy; however, there was no difference between baseline platelet count and current platelet count (P = .5) for the cohort as a whole despite four non-responding patients. Comparing platelet nadir to either baseline platelet count or current platelet count showed a noted difference (P =< .0001) highlighting the significance of the platelet nadirs for the cohort following vaccination Time to treatment response was variable between patients.

After 34 weeks (at the end of the follow-up period), four (24%) of patients continued to have NR to therapy, three patients (17%) had a PR to treatment, and ten patients (59%) had a CR to treatment.

Four patients remained unresponsive to treatment (Figure 3; patients 3, 10, 11, 14) . Of the four non-responsive patients, two patients had a platelet count <100 × 10 9 /L prior to vaccination (88 × 10 9 /L and 96 × 10 9 /L) and two patients had a platelet count >100 × 10 9 /L prior to treatment (190 × 10 9 /L and 312 × 10 9 /L).

Three out of the four patients in the non-responding group experienced bleeding symptoms at presentation. At the time of end of follow-up one patient continued to experience bleeding symptoms and one patient experienced bruising symptoms.

The current COVID-19 pandemic, caused by a novel coronavirus The development of ITP has been noted after vaccines to several infectious agents 23 and most data come from pediatric cohorts; 24 80% of affected children will have a self-limiting clinical course with recovery within 2 months. 25 An incidence of ITP relapse of 6.6% and new ITP diagnosis of 1.4% was noted in this cohort following vaccination. Valuable and recent reviews in this area suggest the risk of relapse appears to vary in the region between 3.3% and 12% and this is important information when counselling and ensuring follow-up of patients. 21, 26, 27 We note numerous similarities in this cohort to recent reports; of note a large proportion of patients appear to require treatment (93% in one cohort) and encouragingly response rates to treatments are high. 20 This cohort did not consist of patients who had undergone splenectomy; however, there is evidence this group has higher risk of relapse and warrants close monitoring post-vaccination. 20 Time to presentation appears to vary 20 It is likely vaccine extension to younger age groups and booster doses are going to become another aspect in the prevention of further surges in COVID-19 in the future. ITP patients with known vaccineassociated relapse will require additional clinical support including monitoring following further vaccination against COVID-19 and reporting such events to relevant regulatory bodies remains essential.

SARS-CoV-2 vaccine-associated ITP relapse is not common, but requires patients to be informed and monitored. In our experience, the incidence of ITP relapse was 6.6% and new diagnosis following vaccination was 1.4%. Ninety-four percent of patients who relapse following vaccination required therapeutic intervention. All patients experienced symptoms of bleeding or bruising and a proportion of patients in this cohort (24%) did not recover their platelet counts to pre-vaccination levels after a median of 17 weeks. The benefit of vaccination continues to outweigh any observed adverse outcomes;

however, a small group of ITP patients will require intervention following vaccination and should be counseled appropriately. 

Hospitalization and mortality among black patients and white patients with Covid-19 | NEJM

Risk factors associated with mortality among patients with covid-19 in intensive care units in Lombardy, Italy | Critical Care Medicine

COVID-19) dashboard

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK -The Lancet

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine

Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination

Immune thrombocytopenia

International consensus report on the investigation and management of primary immune thrombocytopenia

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group

Immune thrombocytopenia in adults: a single-centre review of demographics, clinical features and treatment outcomes

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Thrombosis in COVID-19

Immune thrombocytopenia during the COVID-19 pandemic

Updated international consensus report on the investigation and management of primary immune thrombocytopenia

Thrombopoetin receptor agonist therapy in thrombocytopenia: ITP and beyond

Selective validation of the WHO bleeding scale in patients with chronic immune thrombocytopenia

Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic

Thrombocytopenia following Pfizer and Moderna SARS-CoV -2 vaccination

SARS-CoV-2 vaccination and immune thrombocytopenia in de novo and preexisting ITP patients

Exacerbation of immune thrombocytopenia following COVID-19 vaccination

Immune thrombocytopenic purpura after SARS-CoV-2 vaccine

Luning Prak ET. The ITP syndrome: pathogenic and clinical diversity

Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children

MMR vaccine and idiopathic thrombocytopaenic purpura

Safety of anti-SARS-CoV-2 vaccination for patients with immune thrombocytopenia

SARS-CoV-2 vaccination in patients with autoimmune cytopenias: the experience of a reference center

First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland