Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).

The role of CD8+ T-cell clones in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.

Improving the chances of response to splenectomy in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia. Its pathogenesis is complex relying in large part on destruction of platelets recognized by autoantibodies within the spleen. However, other mechanisms, such as platelet desialylation, may play a role in platelet reduction by accelerating their clearance in the liver. In their study, Mendoza and colleagues reported on platelet scintigraphy performed in 51 ITP patients, showing a response in 87.5% when the sequestration occurred in the spleen versus 45% in case of non-splenic destruction. Platelet desialylation was also measured after splenectomy and found to be higher in non-responder patients. These latter results, while requiring confirmation prior to splenectomy, support platelet desialylation may also be a potential biomarker of non-response to splenectomy. Commentary on: Mendoza et al. Study of platelet kinetics in immune thrombocytopenia to predict splenectomy response. Br J Haematol 2024;204:315-323.

What is the best second-line treatment for immune thrombocytopenia?

The choice between thrombopoietin receptor agonists (TPO-RAs) and anti-CD20 as the preferred second-line therapies for immune thrombocytopenia remains in the eye of the beholders. Each has major advantages and certain weaknesses. Stolz et al. describe a single-centre experience that whets our appetite for a large randomized controlled trial comparing a TPO agonist and an anti-CD20 agent. Commentary on: Stolz et al. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia - A single center retrospective analysis. Br J Haematol 2024; 205:1121-1125.

Immune thrombocytopenia (ITP) in pregnancy.

Immune thrombocytopenia (ITP) in pregnancy is challenging for both mother and fetus. Understanding the pathophysiology, treatments, and risks to the mother and fetus leads to proper management resulting in successful pregnancy and delivery in almost all cases.1 ITP in a pregnant woman has many similarities to ITP not in pregnancy although gestational thrombocytopenia can be confused with ITP. However, recognizing differences is instrumental in avoiding bleeding complications and toxicities of treatment. This Nutshell review focuses on the natural history of ITP in pregnancy, its treatment, and dilemmas.

The highs and lows of cyclic thrombocytopenia.

Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell-mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL, STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia-related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea-induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future.

Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and thus reduces serum IgG concentrations, including autoantibodies. The objective of this study was to evaluate the efficacy and safety of efgartigimod in adults with persistent and chronic primary immune thrombocytopenia. METHODS: This phase 3, multicentre, randomised, double-blinded, placebo-controlled, 24-week study evaluated the efficacy and safety of intravenous efgartigimod in adults aged 18 years or older with chronic or persistent primary immune thrombocytopenia who had an average platelet count of less than 30 000, had responded to at least one previous immune thrombocytopenia therapy, and were on a concurrent therapy at baseline or had received at least a second previous immune thrombocytopenia therapy. The study took place in 71 participating sites from Asia, Europe, and North America. Patients were randomly assigned 2:1 to receive either efgartigimod (10 mg/kg) or placebo intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients' platelet count. The primary endpoint, evaluated in the chronic population, was sustained platelet count response (≥50 × 109 for at least 4 of the last 6 weeks). This study is registered with ClinicalTrials.gov (NCT04188379) and is completed. FINDINGS: A total of 205 patients were screened from Dec 9, 2019, to Feb 3, 2022, and 131 (86 in the efgartigimod group; 45 in the placebo group) were randomly assigned. These patients represented a population with long-term disease who had a mean time since diagnosis of 10·6 years and 67% (88/131) of whom had received at least three previous immune thrombocytopenia treatments. 22% (17/78) of patients with chronic immune thrombocytopenia receiving efgartigimod reached the primary endpoint compared with 5% (2/40) of those receiving placebo (p=0·032; adjusted difference in response, 16% [95% CI 2·6-26·4]). The median number of weeks of disease control in patients with chronic immune thrombocytopenia was 2·0 (IQR 0·0-11·0) for efgartigimod versus 0·0 (0·0-1·0) for placebo (p=0·0009). Efgartigimod was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in efgartigimod and 13% in placebo), haematuria (16% in efgartigimod and 16% in placebo), and petechiae (15% in efgartigimod and 27% in placebo). INTERPRETATION: Efgartigimod significantly increased sustained platelet count responses compared with placebo in patients with chronic immune thrombocytopenia, including those who had received multiple previous immune thrombocytopenia therapies. Upon completion of the ADVANCE IV study, patients could enroll in the ongoing open-label extension. Subcutaneous efgartigimod is currently being evaluated in patients with immune thrombocytopenia in the ADVANCE SC+ trial. FUNDING: argenx.

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.

Familial autoimmunity and risk of developing immune thrombocytopenia and Evans syndrome.

BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

Does anti-HPA-1a affect birthweight in fetal and neonatal alloimmune thrombocytopenia?

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) ensues from parental incompatibility for platelet alloantigens with maternal sensitization. HPA-1a/1b incompatibility is the most common cause of FNAIT in Caucasians. Placental villitis and lower birthweight in FNAIT suggest anti-HPA-1a may have effects beyond inducing thrombocytopenia. OBJECTIVES: Does FNAIT secondary to anti-HPA-1a result in smaller newborns and, the corollary, does antenatal management of FNAIT increase birthweight? STUDY DESIGN: Birthweights of 270 FNAIT-affected newborns from a randomized clinical trial and a NAITbabies.org survey (135 paired siblings) were compared with those of published controls and treated to untreated FNAIT-affected siblings. Birthweights were converted to percentiles to account for gestational age, sex, and role of birth order in birth weight. Body weights of FNAIT-affected and -unaffected pups in a mouse FNAIT model were analyzed. RESULTS: Untreated siblings in both the clinical trial and NAITbabies.org cohorts were not small, compared with normal controls. However, treated siblings in both cohorts had significantly higher birthweight percentiles compared with their previous untreated affected sibling. After accounting for gestational age, sex, and birth order, increased birthweight percentile in treated compared with the untreated siblings remained significant in both cohorts. FNAIT-affected neonatal mice had lower bodyweights than FNAIT-unaffected pups. CONCLUSIONS: Untreated FNAIT-affected newborns were not small; however, treatment of FNAIT-affected pregnancies increased newborn birthweights despite corrections to account for other factors that might have influenced the results. High dose IVIG is believed to "block" FcRn and lower maternal anti-HPA-1a levels, and thus increase birthweights by reducing levels of maternal anti-HPA-1a and reducing placental villitis.

Why should intramuscular anti-D be different from intravenous anti-D?

For reasons of safety the use of intravenous anti D to treat ITP has largely been abandoned because of the risk it incurs of intravascular haemolysis. Intramuscular delivery of anti-D could be a safer approach and deserves to be further evaluated. IV anti-D was a mainstay of ITP treatment in the United States in the 1990's until the development of intravascular hemolysis (IVH) and its serious even fatal consequences was appreciated. Subsequently, treatment of patients with ITP with IV anti-D has become very rare given other alternatives and the IVH risk. IM anti-D does not carry a risk for IVH and it should be re-evaluated and reconsidered as an option for D+ DAT-negative not splenectomized adults who do not have a long duration of ITP and require maintenance treatment. Commentary on: Lakhwani, et al. Intramuscular Anti-D treatment for immune thrombocytopenia: A single centre experience. Br J Haematol 2023;200:353-357.

Treatment of immune thrombocytopenia during pregnancy with thrombopoietin receptor agonists.

The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs are not approved for use during pregnancy due to the absence of evidence and concerns for possible effects on the fetus due to their expected transplacental transfer. This comprehensive review examines the safety and efficacy of TPO-RA in 45 pregnancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same pregnancy n = 2). Mothers experienced failure of the median of three treatment lines during pregnancy prior to TPO-RA administration. A platelet response (>30 × 109 /L) was seen in 86.7% of cases (including a complete response >100 × 109 /L in 66.7%) and was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The maternal safety profile was favourable, with no thromboembolic events encountered. Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal adverse events attributable to TPO-RAs were seen. This review suggests that the use of TPO-RA during pregnancy is associated with a high response rate and appears safe. Nevertheless, TPO-RA should not be routinely used in pregnancy and should be avoided in the first trimester until further evidence is accumulated.

Should dexamethasone alone or in combination be the initial steroid for adult ITP: Still a relevant question.

Corticosteroids are used in first-line treatment in newly diagnosed immune thrombocytopenia. The goal of treatment is primarily to decrease autoantibody-mediated platelet clearance. Ideally initial treatment would not just increase the platelet count but also provide a long-term sustained remission. While many clinicians use prednisone (PDN) as their first choice of corticosteroid, others prefer dexamethasone. The controversy is the subject of debates. Short courses of higher-dose corticosteroids were first reported by the Andersen study in 1994. The study posited high-dose dexamethasone as a 'cure' for all ITP patients. Later, studies addressed the number of dexamethasone cycles, indications to repeat cycles and timing between cycles, with varied long-term results. The results with dexamethasone were compared to PDN in some studies: the four-day cycles of dexamethasone work faster in increasing platelet counts and appear to reduce the occurrence of severe adverse events. Therefore, it is probably a better option for patients with low platelet counts and bleeding diathesis; however, curative superiority, the initial reason to administer it, compared to PDN is not well demonstrated. Across the studies, treatment with high-dose dexamethasone seems to be safer, with lower incidence of all adverse events compared to PDN, which might be a reflection of shorter treatment duration and possibly also lower cumulative steroid dose. Dexamethasone in combination with rituximab in first-line treatment produced higher response rates with better long-term results compared to high-dose dexamethasone alone and is a particularly good option in younger women.

The role of genetics in refractory immune thrombocytopenia.

Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells.

Maintenence rituximab following induction in autoimmune cytopenias.

About 50% of immune thrombocytopenia (ITP) patients respond to rituximab induction, but most relapse. The effectiveness of rituximab maintenance remains untested. This study included autoimmune cytopenia patients who had previously responded to rituximab induction but subsequently relapsed. After re-induction, patients received rituximab maintenance regimen consisting of a single 375 mg/m2 dose administered at 4 month intervals, with a maximum of 6 doses. Primary endpoints were duration of response and safety. Sixteen patients: ITP (9), autoimmune haemolytic anaemia (2), and Evans syndrome (5) received rituximab maintenance. 15/16 achieved complete response (CR); 8/15 CR + 1 partial reponse remain in remission. Median response: 43 months; estimated 5-year relapse-free >50%. Three developed hypogammaglobulinemia. Rituximab maintenance led to prolonged remissions in patients with autoimmune cytopenias who had previously responded to rituximab induction.

B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen.

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Early initiation of second-line therapy in primary immune thrombocytopenia: insights from real-world evidence.

To compare patients with primary immune thrombocytopenia (ITP) prescribed early (within 3 months of initial ITP treatment) second-line treatment (eltrombopag, romiplostim, rituximab, immunosuppressive agents, splenectomy) with or without concomitant first-line therapy to those who received only first-line therapy. This real-world retrospective cohort study of 8268 patients with primary ITP from a large US-based database (Optum® de-identified Electronic Health Record [EHR] dataset) combined electronic claims and EHR data. Outcomes included platelet count, bleeding events, and corticosteroid exposure 3 to 6 months after initial treatment. Baseline platelet counts were lower in patients receiving early second-line therapy (10‒28 × 109/L) versus those who did not (67 × 109/L). Counts improved and bleeding events decreased from baseline in all treatment groups 3 to 6 months after the start of therapy. Among the very few patients for whom follow-up treatment data were available (n = 94), corticosteroid use was reduced during the 3- to 6-month follow-up period in patients who received early second-line therapy versus those who did not (39% vs 87%, p < 0.001). Early second-line treatment was prescribed for more severe cases of ITP and appeared to be associated with improved platelet counts and bleeding outcomes 3 to 6 months after initial therapy. Early second-line therapy also appeared to reduce corticosteroid use after 3 months, although the small number of patients with follow-up data on treatment precludes any substantive conclusions. Further research is needed to determine whether early second-line therapy has an effect on the long-term course of ITP.

Romiplostim use in pregnant women with immune thrombocytopenia.

Treatment for immune thrombocytopenia (ITP) in pregnancy is hampered by the lack of fetal safety evidence of maternally-administered medications. The Pregnancy Surveillance Program (PSP) collected patient information from 2017-2020 for pregnancy, birth outcomes, and adverse events (AEs) for 186 women exposed to romiplostim from 20 days before pregnancy to the end of pregnancy. Timing of exposure was available in 128 women. Seventy-one mothers (38%) had prepregnancy exposure to romiplostim; intrapartum exposure was known for the first (for many mothers when they discovered their pregnancy), second, and third trimesters for 74 (40%), 22 (12%), and 44 (24%) mothers, respectively, with 15 mothers exposed during >1 trimester. Among the 86 mothers with known pregnancy outcomes, 46 (53%) had at least one pregnancy-related serious AE (SAE); approximately 2/3 of SAEs were due to underlying ITP. Of 92 mothers with known birth outcomes, 60 (65%) had a normal pregnancy and 16 (17%) had complications, with both categories including term and preterm births; there were 12 (14%) spontaneous miscarriages/stillbirths, 3 (3%) ectopic pregnancies, and 1 (1%) molar pregnancy. Most abnormal births resulted from abnormal pregnancies. There were five neonatal/postnatal AEs of note: inguinal hernia, cytomegalovirus infection, trisomy 8 (third trimester single-dose romiplostim exposure), single umbilical artery without known anomalies, and development of autism at age 2 years. Seven of 12 infants with neonatal thrombocytopenia had resolution of thrombocytopenia before discharge; all 12 were discharged. Review of pregnancies in women exposed to romiplostim did not reveal any specific safety concerns for mothers, fetuses, or infants.

Effects of COVID-19 vaccination on platelet counts and bleeding in children, adolescents, and young adults with immune thrombocytopenia.

Coronavirus disease 2019 (COVID-19) vaccines rarely cause de novo immune thrombocytopenia (ITP) but may worsen preexisting ITP in adults. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines impact platelet counts and bleeding in children, adolescents, and young adults (C-AYA) with preexisting ITP is unknown. We report here the very limited effect of COVID-19 vaccination on platelet counts and bleeding in a single-center series of 2 C-AYA with ITP. No patient experienced worsening bleeding and only one child had a significant decrease in platelet count which improved spontaneously to her baseline without intervention. SARS-CoV2 vaccination was safe in C-AYA with ITP in this small cohort.

Complement activation negatively affects the platelet response to thrombopoietin receptor agonists in patients with immune thrombocytopenia: a prospective cohort study.

Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.

What is the context?Primary immune thrombocytopenia (ITP) is a potentially serious illness associated with an increased risk of bleeds. Manifestations range from confined skin bruising to life-threatening intracranial hemorrhages.It is an acquired immune disorder characterized by increased destruction and impaired production of platelets.Treatments aim at suppressing the destruction and supporting the production of platelets.Thrombopoietin receptor agonists (TPO-RA) are medically approved platelet growth factors that contribute to the generation of new platelets.The complement system is an evolutionary preserved part of innate immunity.Previous studies have indicated that complement activation may be an important contributor to disease and that the administration of complement-inhibiting therapy improves the platelet count in a subset of patients with primary ITP.What is new? The potential association between complement activation and a poor platelet response to TPO-RA therapy in primary ITP has not been previously studied.In fifteen patients with primary ITP starting TPO-RA therapy, we prospectively followed the platelet response and levels of complement biomarkers for 12 weeks.We showed that patients with high levels of complement biomarkers exhibited a worse treatment response during the study period.What is the impact?Our results suggest that levels of complement biomarkers may be valuable to predict which patients with treatment-refractory ITP that potentially could benefit from complement-inhibiting therapy in the futureLarger studies are needed to confirm our results.