Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow. CD4+ T helper cells are important for B cell differentiation into autoantibody secreting plasma cells. Regulatory Tc are essential to secure immune tolerance, and reduced levels have been implicated in the development of ITP. Both Fcγ-receptor-dependent and -independent pathways are involved in the etiology of ITP. In this review, we present a simplified model for the pathogenesis of ITP, in which exposure of platelet surface antigens and a loss of tolerance are required for development of chronic anti-platelet responses. We also suggest that infections may comprise an important trigger for the development of auto-immunity against platelets in ITP. Post-translational modification of autoantigens has been firmly implicated in the development of autoimmune disorders like rheumatoid arthritis and type 1 diabetes. Based on these findings, we propose that post-translational modifications of platelet antigens may also contribute to the pathogenesis of ITP.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. Our aims were to investigate the effects of COVID-19 vaccination in ITP patients on platelet count, bleeding complications and ITP exacerbation (any of: ≥50% decline in platelet count; or nadir platelet count <30x109/L with >20% decrease from baseline; or use of rescue therapy). Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after first and second vaccination. Linear mixed-effects modelling was applied to analyze platelet counts over time. We included 218 ITP patients (50.9% female, mean age 55 years and median platelet count of 106x109/L) and 200 healthy controls (60.0% female, mean age 58 years and median platelet count of 256x109/L). Platelet counts decreased by 6.3% after vaccination. We observed no difference in decrease between the groups. Thirty ITP patients (13.8%, 95%CI 9.5%-19.1%) had an exacerbation and 5 (2.2%, 95%CI 0.7%-5.3%) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count <50x109/L (OR 5.3, 95%CI 2.1-13.7), ITP treatment at time of vaccination (OR 3.4, 95%CI 1.5-8.0) and age (OR 0.96 per year, 95%CI 0.94-0.99). Our study highlights safety of COVID-19 vaccination in ITP patients and importance of close monitoring platelet counts in a subgroup of ITP patients. ITP patients with exacerbation responded well on therapy.

Retinal inflammation plays a key role in the progression of age-related macular degeneration (AMD), a condition that leads to loss of central vision. The deposition of the acute phase pentraxin C-reactive protein (CRP) in the macula activates the complement system, thereby contributing to dysregulated inflammation. The complement protein factor H (FH) can bind CRP and down-regulate an inflammatory response. However, it is not known whether a truncated form of FH, called factor H-like protein 1 (FHL-1), which plays a significant regulatory role in the eye, also interacts with CRP. Here, we compare the binding properties of FHL-1 and FH to both CRP and the related protein pentraxin-3 (PTX3). We find that, unlike FH, FHL-1 can bind pro-inflammatory monomeric CRP (mCRP) as well as the circulating pentameric form. Furthermore, the four-amino acid C-terminal tail of FHL-1 (not present in FH) plays a role in mediating its binding to mCRP. PTX3 was found to be present in the macula of donor eyes and the AMD-associated Y402H polymorphism altered the binding of FHL-1 to PTX3. Our findings reveal that the binding characteristics of FHL-1 differ from those of FH, likely underpinning independent immune regulatory functions in the context of the human retina.

Background Platelets play a key role in hemostasis through plug formation and secretion of their granule contents at sites of endothelial injury. Defects in von Willebrand factor (VWF), a platelet α‐granule protein, are implicated in von Willebrand disease (VWD), and may lead to defective platelet adhesion and/or aggregation. Studying VWF quantity and subcellular localization may help us better understand the pathophysiology of VWD. Objective Quantitative analysis of the platelet α‐granule compartment and VWF storage in healthy individuals and VWD patients. Patients/Methods Structured illumination microscopy (SIM) was used to study VWF content and organization in platelets of healthy individuals and patients with VWD in combination with established techniques. Results SIM capably quantified clear morphological and granular changes in platelets stimulated with proteinase‐activated receptor 1 (PAR‐1) activating peptide and revealed a large intra‐ and interdonor variability in VWF‐positive object numbers within healthy resting platelets, similar to variation in secreted protein acidic and rich in cysteine (SPARC). We subsequently characterized VWD platelets to identify changes in the α‐granule compartment of patients with different VWF defects, and were able to stratify two patients with type 3 VWD rising from different pathological mechanisms. We further analyzed VWF storage in α‐granules of a patient with homozygous p .C1190R using electron microscopy and found discrepant VWF levels and different degrees of multimerization in platelets of patients with heterozygous p .C1190 in comparison to VWF in plasma. Conclusions Our findings highlight the utility of quantitative imaging approaches in assessing platelet granule content, which may help to better understand VWF storage in α‐granules and to gain new insights in the etiology of VWD.

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder against platelets characterized by a low platelet count and increased bleeding risk. ITP is likely to rise from defective immune tolerance in addition to a triggering event, such as vaccination. COVID-19 vaccination is associated with a small increased risk of development of de novo ITP. In patients historically diagnosed with ITP, relapse of thrombocytopenia after COVID-19 vaccination has been described. However, the precise platelet dynamics in previously diagnosed ITP patients after COVID-19 vaccination is unknown Aims: To investigate the effect of the COVID-19 vaccine on platelet count, the occurrence of severe bleeding complications and necessity of rescue medication in patients historically diagnosed with ITP. Methods: Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after the first and second vaccination. Linear mixed effects modelling was applied to analyse platelet count dynamics over time. Results: We included 218 ITP patients (50.9% women) with a mean (SD) age of 58 (17) years and 200 healthy controls (60.0% women) with a mean (SD) age of 58 (13) years. Healthy controls and ITP patients had similar baseline characteristics (Table 1). 201/218 (92.2%)ITP patients received the mRNA-1273 vaccine, 16/218 (7.3%) the BNT162b vaccine and 1/218 (0.46%) the Vaxzevria vaccine. All healthy controls received the mRNA-1273 vaccine. Fifteen (6.8%) patients needed rescue medication (Table 1). Significantly more ITP patients who needed rescue medication were on ITP treatment prior COVID-19 vaccination compared to patients without exacerbation (56.2% (7/16) vs 27.4% (55/202), p=0.016). We found a significant effect of vaccination on platelet count over time in both ITP patients and healthy controls (Figure 1A). Platelet counts of ITP patients decreased 7.9% between baseline and 4 weeks after second vaccination (p=0.045). Rescue medication and prior treatment significantly increased platelet count over time (p=0.042 and p=0.044). Healthy controls decreased 4.5% in platelet count (p<0.001) between baseline and 4 weeks after second vaccination. There was no significant difference in platelet count between ITP patients and healthy controls (p=0.78) (Figure 2). IPT patients with a baseline platelet count of >150x10 9/L had a significant decrease of platelet count 4 weeks after second vaccination compared to baseline (median platelet count (IQR) 205 (94) vs 203 x10 9/L (109) p=0.001). No significant decrease was seen in ITP patients with a baseline platelet count <150 x10 9/L. Median (IQR) platelet counts were similar between patients with and without exacerbation, except for 4 weeks after second vaccination (112 (105) vs 45 x 10 9/L (70), p=0.025) (Figure 1B). No significant effect was observed over time in ITP patients with rescue medication (p=0.478) (Figure 1C). In ITP patients without rescue medication, COVID-19 vaccination had a significant effect over time (p=0.001), especially 1 week after second vaccination (Figure1B). Of the 15 patients who needed rescue medication, 8/15 patients (53.3%) received rescue medication within 4 weeks after first vaccination and 4/15 (26.67%) needed rescue medication after the first as well as after the second vaccination. 3/15 (20.0%) patients needed rescue medication after the second vaccination. In the total ITP population, 5/218 (2.2%) experienced a WHO grade 2-4 bleeding complication and 3/218 (1.4%) needed platelet transfusion. 4/5 (80%) bleedings occurred before the second vaccination. One of these patients had fatal varices bleeding, although platelet count was normal. Conclusion: COVID-19 vaccination has a significant effect on platelet count in ITP patients and healthy controls. In 6.8% of ITP patients rescue medication was needed and in 2.2% of ITP patients a WHO grade 2-4 bleeding occurred. The majority of rescue medication was given and the majority bleeding complications occurred in the 4 weeks after the first vaccination. Our results demonstrate that close monitoring of platelet count after COVID-19 vaccination is important in patients historically diagnosed with ITP. Figure 1 Figure 1. Disclosures Westerweel: Pfizer: Consultancy; BMS / Celgene: Consultancy; Incyte: Consultancy; Novartis: Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kruip: Bayer: Honoraria, Research Funding; Daiichi Sankyo: Research Funding. Jansen: Novartis: Consultancy, Other: Travel, Accommodations, Expenses; Advisory Board Novartis: Membership on an entity's Board of Directors or advisory committees; 3SBIO, Novartis: Other: Travel, accomodations, expenses.

Summary Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes.

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