The Pitfalls of Global Hemostasis Assays in Myeloproliferative Neoplasms and Future Challenges.

Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies.

Association of patient, treatment and disease characteristics with patient-reported outcomes: Results of the ECHO Registry.

INTRODUCTION: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen. AIM: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA. METHODS: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses. RESULTS: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores. CONCLUSION: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being.

PFA-100 System: A New Method for Assessment of Platelet Dysfunction.

This is a celebratory reprint of a historical paper published in STH in 1998. The original Abstract follows.The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature (mean closure time [CT] of 132 seconds for CEPI and 93 seconds for CADP). The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the receiver operating characteristic curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects.

Emicizumab: the hemophilia A game changer.

In hemophilia, the unmet needs regarding adherence to prophylaxis and lack of effective longterm prophylaxis regimens, especially in patients with inhibitors, led to the production of emicizumab, the first non-factor medicine for subcutaneous administration in patients with severe and moderate hemophilia A with or without factor VIII inhibitors. This article describes the research steps behind the development of this game-changer medication, its success for the prophylaxis of bleeding episodes as witnessed by the results of pivotal clinical trial but also by real life use in the frame of a still expanding global market. We shall also discuss potential and actual adverse events and the nuances related to clinical use such as laboratory monitoring, development of neutralizing anti-drug-antibodies, risk of thrombosis/hypercoagulability and use in the management of surgical operations. The potential of using emicizumab to prevent bleeding in other congenital and acquired coagulation disorders will also be sketched.

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8-mutation-effects and non-F8-genetics.

Clinical efficacy of simoctocog alfa versus extended half-life recombinant FVIII concentrates in hemophilia A patients undergoing personalized prophylaxis using a matching-adjusted indirect comparison method.

OBJECTIVES: We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates. METHODS: Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. RESULTS: A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%. CONCLUSIONS: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less.

Corrigendum to 'Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis' [Research and Practice in Thrombosis and Haemostasis, Volume 7, Issue 2, February 2023, 100077].

[This corrects the article DOI: 10.1016/j.rpth.2023.100077.].

Bleeding events in people with congenital haemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: A systematic literature review.

BACKGROUND: Evidence on bleeding rates in people with congenital haemophilia A (PwcHA) without inhibitors on factor VIII (FVIII) replacement products is inconsistent. AIM: This systematic literature review assessed bleeding outcomes in PwcHA using FVIII-containing products as prophylactic treatment. METHODS: A search was conducted using the bibliographic databases Medline, Embase and Cochrane Central Register of Controlled Trials on the Ovid platform. The search involved a bibliographic review of clinical trial studies, routine clinical care studies and registries and a search of ClinicalTrials.gov, EU Clinical Trials Register and conference abstracts. RESULTS: The search yielded 5548 citations. A total of 58 publications were included for analysis. In 48 interventional studies, the pooled estimated mean (95% confidence interval [CI]) annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) and proportion of participants with zero bleeding events were 3.4 (3.0-3.7), 2.0 (1.6-2.5), and 38.5% (33.1-43.9), respectively. In 10 observational studies, the pooled estimated mean (95% CI) ABR, AJBR and proportion of participants with zero bleeding events were 4.8 (4.0-5.5), 2.6 (2.1-3.2), and 21.8% (19.9-47.5), respectively. A large variation in mean effect size for ABR, AJBR and zero bleeding event data across cohorts and cohort types was observed. Funnel plots indicated potential reporting bias for publications incorporating ABR and AJBR data across both interventional and observational studies. CONCLUSION: This meta-analysis shows that PwcHA without inhibitors still have bleeds despite FVIII prophylaxis. Improved standardization on capturing and reporting bleeding outcomes is needed so that effective comparisons between treatments can be made.

Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis.

Background: Across the HAVEN clinical trial program, the efficacy of emicizumab has been demonstrated in children, adolescents, and adults with hemophilia A, with or without factor VIII inhibitors. After the 4-week loading dose period, emicizumab concentrations are expected to remain at levels that provide bleed protection throughout the entire dosing interval, regardless of the chosen maintenance dosing regimen, ie, weekly, every 2 weeks, or every 4 weeks. Objectives: The objective of this study was to examine the timing of treated bleeds within the dosing intervals for emicizumab administered during the HAVEN 1 to 4 studies. Methods: In this post hoc analysis, we pooled data from all the participants of the HAVEN 1 to 4 studies and analyzed the timing of treated bleeds in relation to the emicizumab dose. Results: A total of 392 participants were included in this analysis, with a median (range) age of 28.0 years (1.1-77.0 years). Target joints were identified in 237 of 392 (60.5%) participants before the study entry. Overall, 211 of 392 (53.8%) participants experienced 907 treated bleeding events. The total mean (SD) annualized bleeding rate across the 4 studies was 1.6 (5.9). There was no evidence that bleeding events clustered on any 1 particular day in any dosing schedule from HAVEN 1 to 4 (P > .05 for all 3 treatment regimens). Conclusion: Data from the HAVEN 1 to 4 trials show consistent bleed prevention within the dosing interval, regardless of the dosing regimen chosen. These findings provide further evidence of the sustained efficacy of emicizumab across all approved dosing regimens to reduce bleeding in people with hemophilia A.

Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib.

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.

Immune thrombocytopenia (ITP) is an autoimmune disease that usually happens when your immune system mistakenly attacks and destroys platelets, which are cells that help blood to clot. Individuals with ITP can experience easy or excessive bruising and bleeding. Scientists have identified that an enzyme called spleen tyrosine kinase (SYK) is involved in numerous biological processes that are associated with the immune system response, inflammation, and some types of cancer in humans. Therefore, it has become a target for new drugs which inhibit the action of SYK. In this review article, the authors provide a summary of the biological properties and actions of SYK and its involvement in various diseases, discuss information about drugs that have been developed as SYK inhibitors for the treatment of ITP, and consider other potential uses for drugs that inhibit SYK. Although several drugs are being developed, the only SYK inhibitor that is currently available for the treatment of ITP is a drug called fostamatinib. In patients with ITP, including those who no longer respond to other treatments, fostamatinib has been shown to improve platelet counts and reduce bleeding events. Researchers are also currently investigating the use of drugs that inhibit SYK, including fostamatinib, for the potential treatment of other diseases associated with inflammation (e.g. rheumatoid arthritis, COVID-19), autoimmunity (e.g. warm autoimmune hemolytic anemia), and blood cancers (e.g. lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia).

Patient-reported outcomes of patients with myelofibrosis or essential thrombocythemia enrolled in the MOST study.

The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) is an ongoing, noninterventional study assessing clinical characteristics and patient-reported outcomes (PROs) of patients with myelofibrosis (MF) or essential thrombocythemia (ET). This analysis assessed PROs at enrollment; symptom burden and quality of life (QoL), work productivity, and activity were assessed using validated questionnaires in patients with low- or intermediate-1-risk (age-alone) MF, or high- or low-risk ET (receiving ET-directed therapy) at enrollment. In MF and ET cohorts, fatigue had highest mean symptom score. Women had higher mean total symptom scores (TSS), mean symptom scores, and reduced QoL versus men. In patients with MF, mean TSS and symptom scores were similar between risk groups. Patients with low-risk ET had higher mean TSS and symptom scores than patients with high-risk ET. In conclusion, patients with lower risk MF and low- or high-risk ET experience significant symptom burden affecting QoL and ability to work.

First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.

Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1-3.

Background: Bleeding in people with hemophilia A can be life threatening, and intra-articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported. Objectives: We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice. Patients/Methods: Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial. Results: In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra-individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis. Conclusion: A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

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 preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) 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] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting 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 patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting 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 postsplenectomy and with more refractory disease, is indicated.