Bleeding self-assessments by patients with immune thrombocytopenia (ITP): An agreement study.

We designed anagreement study to compare the results of bleeding assessments done in tandem by ITP patients and trained research staff. We used a modified version of the ITP Bleeding Scale, which captured the patients' worst bleeding event at any of nine anatomical sites since the time of the last assessment. Interrater agreement was determined using the 2-way kappa for the assessment of severe vs. non-severe bleeds. We analyzed 108 consecutive patients with ITP from the McMaster ITP Registry who had duplicate bleeding assessments. Two-way agreement was excellent for gynecological (k = 0.86, 95% CI 0.71-1.02), gastrointestinal (k = 1), genitourinary (k = 1), pulmonary (k = 1) and intracranial (k = 1) bleeds; good for skin (k = 0.68, 95% CI, 0.54-0.82), oral (k = 0.76, 95% CI, 0.53-0.98) and ocular (k = 0.66, 95% CI, 0.04-1-28) bleeds; and moderate for epistaxis (k = 0.58, 95% CI, 0.21-0.95). Bleeding self-assessments by ITP patients were similar to trained research staff, but disagreements in severity grades were more frequent with skin bleeds, oral bleeds and epistaxis. Bleeding self-assessments could simplify bleeding assessments in clinical trials.

A case of acquired transient bleeding diathesis associated with acquired platelet storage pool deficiency and defective thromboxane A2 production.

Acquired disorders of platelet function are an underdiagnosed cause of bleeding tendency. A 14-year-old girl developed moderate mucocutaneous bleeding two weeks after a Mycoplasma pneumoniae infection successfully treated with clarithromycin. The patient was referred to us 7 months later for laboratory investigation of the persisting bleeding diathesis. The patient's personal and family histories were negative for bleeding disorders. Complete blood count, von Willebrand Factor levels and coagulation tests were normal; platelet aggregation, ATP secretion, δ-granules content and serum thromboxane B2 levels were defective. At follow-up visits, laboratory parameters and the bleeding diathesis progressively normalized within 2 years. The patient's condition is compatible with a diagnosis of acquired Storage Pool Deficiency (SPD), associated with defective thromboxane A2 production. To our knowledge, this is the first case of acquired, transient SPD with spontaneous remission. The pathogenic role of Mycoplasma pneumoniae infection or clarithromycin is possible, albeit uncertain.

Refractory immune thrombocytopenia in adults: Towards a new definition.

Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune-mediated thrombocytopenia and a variable risk of bleeding. Despite the availability of multiple treatment options, some patients are considered refractory since they do not achieve a platelet count response to multiple treatments and are at risk of bleeding. The term 'refractory' has been used to identify this patient group; however, with the advent of multiple lines of treatment, its meaning has become ambiguous. To address this issue, we reviewed previous definitions of refractory ITP, solicited the views of ITP experts and collected data from registries to inform a definition. Twenty ITP experts who attended the 7th Expert Meeting of the Intercontinental Cooperative ITP Study Group in September 2022 answered a web-based survey: 95% felt that there was a need for a new definition of refractory ITP for clinical and research purposes. The use of the term refractory, accompanied by a clear indication of the type and timing of failed treatments, was supported by 85% of respondents. Preliminary data on the frequency of refractory patients from the McMaster and Norwegian ITP Registries demonstrated that the proportion of adult ITP patients who had failed first-line therapy, rituximab, thrombopoietin receptor agonists, any immune suppressant medication and splenectomy ranged from 0.4% to 3.8%. We propose a definition of refractory ITP that could be evaluated in future studies.

Impairment of platelet function in both mild and severe COVID-19 patients.

Abnormalities of platelet function were reported in patients with severe COVID-19 (severe-C), but few data are available in patients with mild COVID-19 (mild-C) and after COVID-19 recovery. The aim of this study was to investigate platelet parameters in mild-C patients (n = 51), with no evidence of pneumonia, and severe-C patients (n = 49), during the acute phase and after recovery, compared to 43 healthy controls. Both mild-C and severe-C patients displayed increased circulating activated platelets, low δ-granule content (ADP, serotonin), impaired platelet activation by collagen (light transmission aggregometry) and impaired platelet thrombus formation on collagen-coated surfaces under controlled flow conditions (300/s shear rate). The observed abnormalities were more marked in severe-C patients than in mild-C patients. Overall, 61% (30/49) of mild-C and 73% (33/45) of severe-C patients displayed at least one abnormal platelet parameter. In a subgroup of just 13 patients who showed no persisting signs/symptoms of COVID-19 and were re-evaluated at least 1 month after recovery, 11 of the 13 subjects exhibited normalization of platelet parameters. In conclusion, mild abnormalities of platelet parameters were present not only in severe-C but also, albeit to a lesser extent, in mild-C patients during the acute phase of COVID-19 and normalized in most tested patients after clinical recovery.

Thrombosis and Bleeding in Patients with Vaccine-Induced Immune Thrombotic Thrombocytopenia: A Systematic Review of Published Cases.

INTRODUCTION: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic reaction to COVID-19 (coronavirus disease 2019) adenoviral vector vaccines. Its distinct bleeding and thrombotic patterns compared with other platelet consumptive disorders remain unclear. METHODS: We performed a systematic review of the literature (PubMed and Embase) up to July 31, 2022, including case reports and case series providing nonaggregate data of VITT patients. Accurate VITT diagnosis required fulfillment of the following criteria: (1) endorsement by the authors, (2) consistent vaccine type and timing, (3) presence of thrombocytopenia and thrombosis, (4) detection of anti-platelet factor 4 antibodies. Data are presented as frequencies with 95% confidence intervals (CIs) calculated with the exact binomial method. RESULTS: We retrieved 143 eligible studies, describing 366 patients. Of 647 thrombotic events, 53% (95% CI: 49-56) were venous thromboses at unusual sites and 30% (95% CI: 27-34) were cerebral venous sinus thromboses (CVSTs). The ratio of venous-to-arterial events was 4.1. Thromboses in most sites were associated with at least another thrombotic event, with the exception of CVST and CNS arterial thrombosis (isolated in 49 and 39% of cases, respectively). Bleeding occurred in 36% (95% CI: 31-41) of patients; 68% (95% CI: 59-75) of bleeding events were intracranial hemorrhages (ICHs). Overall mortality was 24% (95% CI: 19-29), and 77% (95% CI: 58-90) in patients with isolated CVST complicated by ICH. CONCLUSION: VITT displays a venous-to-arterial thrombosis ratio comparable to heparin-induced thrombocytopenia. However, VITT is characterized by a higher prevalence of CVST and ICH, which contribute to the increased bleeding frequency and mortality.

Pharmacological Efficacy and Gastrointestinal Safety of Different Aspirin Formulations for Cardiovascular Prevention: A Narrative Review.

Aspirin inhibits platelet function by irreversibly inhibiting the synthesis of thromboxane A2 (TxA2). Aspirin, at low doses, is widely used for cardiovascular prevention. Gastrointestinal discomfort, mucosal erosions/ulcerations and bleeding are frequent complications of chronic treatment. To reduce these adverse effects, different formulations of aspirin have been developed, including enteric-coated (EC) aspirin, the most widely used aspirin formulation. However, EC aspirin is less effective than plain aspirin in inhibiting TxA2 production, especially in subjects with high body weight. The inadequate pharmacological efficacy of EC aspirin is mirrored by lower protection from cardiovascular events in subjects weighing >70 kg. Endoscopic studies showed that EC aspirin causes fewer erosions of the gastric mucosa compared to plain aspirin (which is absorbed in the stomach) but causes mucosal erosions in the small intestine, where it is absorbed. Several studies demonstrated that EC aspirin does not reduce the incidence of clinically relevant gastrointestinal ulceration and bleeding. Similar results were found for buffered aspirin. Although interesting, the results of experiments on the phospholipid-aspirin complex PL2200 are still preliminary. Considering its favorable pharmacological profile, plain aspirin should be the preferred formulation to be used for cardiovascular prevention.

Unique features of vaccine-induced immune thrombotic thrombocytopenia; a new anti-platelet factor 4 antibody-mediated disorder.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic disorder caused by anti-PF4 antibodies that activate platelets and neutrophils, leading to thrombosis. Heparin-induced thrombocytopenia (HIT) is a related anti-PF4 mediated disorder, with similar pathophysiology and clinical manifestations but different triggers (i.e., heparin vs adenoviral vector vaccine). Clinically, both HIT and VITT typically present with thrombocytopenia and thrombosis, although the risk of thrombosis is significantly higher in VITT, and the thromboses occur in unusual anatomical sites (e.g., cerebral venous sinus thrombosis and hepatic vein thrombosis). The diagnostic accuracy of available laboratory testing differs between HIT and VITT; for VITT, ELISAs have better specificity compared to HIT and platelet activation assays require the addition of PF4. Treatment of VITT and HIT is anticoagulation non-heparin anticoagulants; however, heparin may be considered for VITT if no other option is available.

Sensitivity of SARS-CoV-2 Detection With Nasopharyngeal Swabs.

Background: SARS-CoV-2-infected subjects have been proven contagious in the symptomatic, pre-symptomatic and asymptomatic phase. The identification of these patients is crucial in order to prevent virus circulation. No reliable data on the sensitivity of nasopharyngeal swabs (NPS) are available because of the lack of a shared reference standard to identify SARS-CoV-2 infected patients. The aim of our study was to collect data on patients with a known diagnosis of COVID-19 who underwent serial testing to assess NPS sensitivity. Methods: The study was a multi-center, observational, retrospective clinical study with consecutive enrollment. We enrolled patients who met all of the following inclusion criteria: clinical recovery, documented SARS-CoV-2 infection (≥1 positive rRT-PCR result) and ≥1 positive NPS among the first two follow-up swabs. A positive NPS not preceded by a negative nasopharyngeal swab collected 24-48 h earlier was considered a true positive. A negative NPS followed by a positive NPS collected 24-48 h later was regarded as a false negative. The primary outcome was to define sensitivity of SARS-CoV-2 detection with NPS. Results: Three hundred and ninety three NPS were evaluated in 233 patients; the sensitivity was 77% (95% CI, 73 to 81%). Sensitivity of the first follow-up NPS (n = 233) was 79% (95% CI, 73 to 84%) with no significant variations over time. We found no statistically significant differences in the sensitivity of the first follow-up NPS according to time since symptom onset, age, sex, number of comorbidities, and onset symptoms. Conclusions: NPS utility in the diagnostic algorithm of COVID-19 should be reconsidered.