Catastrophic Bleeding in Immune Thrombocytopenia: Insights from Four Adult Cases of Intracranial Hemorrhage

Immune Thrombocytopenia during Childhood: New Approaches to Classification and Management

Interleukin-37 reduces inflammation and impairs phagocytosis of platelets in immune thrombocytopenia (ITP)

Background:Immune thrombocytopenia (ITP) is an autoimmune and inflammatory disease characterized by low platelet count with heterogeneous bleeding manifestations. Severe bleeding in ITP is not completely related with low platelet count. Thus, there is a great need for reliable indicators of the susceptibility of bleeding in ITP patients. Interleukin‐37 (IL‐37) is an anti‐inflammatory cytokine that participates in the process of several inflammatory and autoimmune diseases. However, the role of IL‐37 in the pathogenesis of ITP is unknown.Aims:Our study aimed to evaluate the regulatory role of IL‐37 in the process of ITP and its association with disease severity.Methods:Plasma IL‐37 was detected by enzyme‐linked immunosorbent assay (ELISA). We cultured the monocytes/macrophages from ITP patients to investigate the regulatory role of IL‐37 on monocytes/macrophages. Fcγ receptors (FcγRs) of macrophages were analyzed using flow cytometry and q‐PCR. Signaling pathways were determined by western blotting. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets.Results:Plasma and mRNA levels of the anti‐inflammatory cytokine IL‐37 were elevated in ITP patients with platelet counts below 30 × 109 /L compared to healthy controls and to ITP patients with platelet counts above 30 × 109 /L. Furthermore, plasma IL‐37 levels correlated with the platelet number and IBLS bleeding scores of ITP patients. Specifically, ITP patients with skin and oral bleeding symptoms had higher plasma IL‐37 levels than patients without these bleeding symptoms. Patients with more severe skin and oral bleeding exhibited higher plasma IL‐37 levels, indicating that IL‐37 could be a candidate in evaluating disease severity of ITP. IL‐37 initiated an anti‐inflammatory effect on monocytes/macrophages from ITP patients by down‐regulating the phosphorylation of MAPK, AKT, and NF‐κB signaling pathways, which are pivotal in mediating inflammation. Moreover, IL‐37 restored the balance of activating and inhibitory FcγRs (Figure 1) and decreased antibody‐mediated platelet phagocytosis by monocytes/macrophages, suggesting that IL‐37 might be a potential therapeutic agent in ITP.Summary/Conclusion:Our study demonstrated that ITP patients exhibited higher IL‐37 expression, especially patients with severe hemorrhage or low platelet count. IL‐37 decreased antibody‐mediated platelet phagocytosis, restored the balance of activating and inhibitory FcγRs, and inhibited inflammatory activity via MAPK, AKT, and NF‐κB signaling pathways among monocytes/macrophages. Therefore, IL‐37 might be a candidate in evaluating the severity of ITP and a promising therapeutic agent for the management of ITP.image

Urgent Management of Bleeding in Immune Thrombocytopenia: Towards a Standardized Protocol in the Emergency Department

Risk factors for skin, mucosal, and organ bleeding in adults with primary ITP: a nationwide study in Japan

Bleeding is the most important clinical outcome in patients with immune thrombocytopenia (ITP), and the goal of therapy in such cases is to treat or prevent bleeding. The frequency of and risk factors for bleeding events in ITP have only recently been identified in several large-scale studies. However, there is little published information about severe life-threatening bleeding in ITP. To clarify the clinical features of life-threatening bleeding in patients with primary ITP, we systematically reviewed the medical records of all ITP patients that were admitted to our hospital between January 1, 1992, and December 31, 2015. Of 169 consecutive inpatients with primary ITP, 8 suffered life-threatening bleeding (10 episodes: gastrointestinal, 4 cases; pulmonary, 1 case; and intracranial, 5 cases). All of these patients were ≥ 60years of age and had platelet counts of < 20×109/L. The highest incidence of such bleeding was found among elderly patients in their 80s with platelet counts of < 5×109/L. Among the patients aged ≥ 60years with platelet counts of < 20×109/L, the background data of the patients with and without life-threatening bleeding episodes were compared. It was shown that the patients in the bleeding group were older than those in the non-bleeding group (80.13±2.31 vs. 73.39±2.51years, p=0.0266). Hypertension, diabetes mellitus, anticoagulant use, ITP phase, and sex were not identified as strong risk factors for life-threatening bleeding. Combining age and the platelet count might be a useful way of identifying ITP patients that are at risk of life-threatening bleeding. Most intracranial hemorrhaging (4/5) was spontaneous and multifocal, suggesting that these might be characteristics of ITP-related bleeding in elderly patients.

A Multicenter Study Evaluating the Safety of Romiplostim at Maximal Dosage for Emergency Bleeding Situations in Immune Thrombocytopenia

Association of Platelet Count and Mean Platelet Volume with Severity of Bleeding Events in Patients with Immune Thrombocytopenia

Evaluation of Bleeding Self-Assessments By Patients with Immune Thrombocytopenia (ITP): An Agreement Study

This study presents the results of a real-life, multicenter, prospective, post-approval safety evaluation of Clairyg® 50 mg/mL, a 5% intravenous immunoglobulin (IVIg) liquid, in 59 children (aged < 12 years) with primary immunodeficiency diseases (PID) (n = 32) or immune thrombocytopenia (ITP) (n = 27) in France. The primary objective of the study was to assess the safety and tolerability of Clairyg®, recording all serious and non-serious adverse events (AEs), whether related (rAEs) or not related to the product. Secondary objectives aimed at evaluating the administration of Clairyg® under routine conditions and the available efficacy data to better document the benefit/risk ratio in this pediatric population. An exploratory objective was added to evaluate the potential factors associated with the occurrence of rAEs. Patients received Clairyg® according to the approved dosage under normal conditions of prescriptions over a median follow-up period of 11.8 months. A total of 549 infusions (PID: n = 464 and ITP: n = 85), were administered, of which 58.8% were preceded by premedication. The most frequent rAEs were headache, vomiting, and pyrexia in both indications. Most of them were considered non-serious and mild or moderate in intensity. A severe single rAE was observed (aseptic meningitis) in a 4-year-old girl presenting with chronic ITP. The exploratory multivariate analysis of potential co-factors showed that the occurrence of rAEs is significantly linked to high IVIg doses and possibly to female gender. The annualized rate of serious bacterial infections was 0.11 for patients with PID. For patients with ITP, 74.1% experienced at least one bleeding episode during the follow-up, mostly a cutaneous one, and none had gastrointestinal, genitourinary, or central nervous system bleeding. Clairyg® was well tolerated and allowed for control of serious bacterial infection in PID and serious bleeding in ITP, which are the main complications in these respective pediatric disorders. No new safety signal was detected in children less than 12 years-old in real-life conditions of use.

Comparison of Bleeding Tools in a Cohort of Pediatric Patients with ITP: Data from the Pediatric ITP Consortium of North America ICON1 Study

Treatment decisions for patients with immune thrombocytopenia (ITP) are difficult because patients with similarly low platelet counts differ in their bleeding tendency. We recently reported that platelet function tests, independent of platelet count, are associated with concurrent bleeding severity, suggesting that these tests may be useful indicators of future bleeding in ITP. To test this hypothesis, we evaluated the consistency of these platelet function tests over time and their association with subsequent bleeding severity. Bleeding score and platelet biomarkers were evaluated in a cross-sectional study of children with ITP at two visits separated by a median of 10 months. Correlations between Visit 1 and Visit 2 results for immature platelet fraction, circulating and agonist-stimulated platelet surface P-selectin, and activated GPIIb-IIIa and GPIbα indicated consistency of the platelet phenotype over time. Consistent with our previous findings, platelet biomarkers at each visit were significantly associated with the concurrent bleeding score. Furthermore, increased P-selectin on circulating platelets and reduced agonist-stimulated P-selectin and activated GPIIb-IIIa-positive platelets at Visit 1 were significantly associated with bleeding scores at Visit 2 and remained significantly associated with bleeding severity after adjustment for platelet count. These results suggest a mechanistic link between desensitization of agonist receptors and increased bleeding severity. In summary, platelet function in ITP, independent of platelet count, is consistent over time and is associated with both concurrent and subsequent bleeding severity. These findings support further evaluation of platelet function testing to help guide patient management in ITP.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Diagnosis of immune thrombocytopenia (ITP) and prediction of response to therapy remain significant and constant challenges in hematology. In patients who present with ITP, the platelet count is frequently used as a surrogate marker for disease severity, and so often determines the need for therapy. Although there is a clear link between thrombocytopenia and hemostasis, a direct correlation between the extent of thrombocytopenia and bleeding symptoms, especially at lower platelet counts is lacking. Thus, bleeding in ITP is heterogeneous, unpredictable, and nearly always based on a multitude of risk factors, beyond the platelet count. The development of an evidence-based, validated risk stratification model for ITP treatment is a major goal in the ITP community and this review discusses new laboratory approaches to evaluate the various pathobiologies of ITP that may inform such a model.

Clinical Epidemiology and First-Line Treatment in Immune Thrombocytopenia Adults. Results of the Carmen Prospective Cohort