IVIg-exposure and thromboembolic event risk: findings from the UK Biobank.

BACKGROUND: Arterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig. METHODS: We included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively.  FINDINGS: 14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE. INTERPRETATION: Intravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure.

Pharmacological venous thromboembolism prophylaxis in elective cranial surgery: a systematic review of time of initiation, regimen and duration.

INTRODUCTION: Pharmacological prophylaxis of venous thromboembolism (VTE) requires nuanced decision-making to balance the risk of VTE against haemorrhage. This problem is compounded in neurosurgical patients, in whom postoperative intracranial haemorrhage (ICH) may be catastrophic, compared to non-neuraxial bleeding in other types of surgery. Current major guidelines recommend caution when using pharmacological prophylaxis in elective cranial surgery, but incorporate low-quality evidence and lack precise guidance on timing and duration of anticoagulation. METHODS: We aimed to answer the following questions for patients undergoing elective cranial surgery: (1) when is the optimal time to initiate postoperative anticoagulation, and (2) how long should postoperative anticoagulation be continued for? In this systematic review, we screened randomised and non-randomised studies reporting original data on pharmacological VTE prophylaxis in elective cranial surgery. Outcomes of interest were VTE and ICH. RESULTS: Three retrospective, single-centre observational studies met eligibility criteria, with a total of 923 participants. Meta-analysis was not performed due to a high risk of bias across all studies. Through narrative synthesis, we found that patients who developed VTE were significantly more likely to receive their first postoperative dose at a later time (mean: 144 vs. 29 h, p = .04). Shorter courses of anticoagulation (<7 days) were associated with significantly lower ICH rates (p = .03) compared to longer courses (>21 days). CONCLUSION: The limited evidence favours earlier initiation and shorter courses of thromboprophylactic anticoagulation. These findings are specific to patients undergoing surgery for meningioma or glioma and may not apply to other populations. Randomised controlled trials or robustly designed observational studies are necessary to establish a clearer evidence base.

Tapering and Discontinuation of Thrombopoietin Receptor Agonist Therapy in Patients with Immune Thrombocytopenia: Results from a Modified Delphi Panel.

BACKGROUND: Recent evidence suggests that in patients with immune thrombocytopenia (ITP) with a stable response on thrombopoietin receptor agonists, treatment may be tapered and/or discontinued. OBJECTIVES: The objective of this study was to provide a guide for tapering and discontinuation of TPO-RA therapy in patients with ITP, based on hematologist survey results, existing evidence, and expert consensus. PATIENTS/METHODS: UK hematologists completed a survey to characterize self-reported practice patterns related to TPO-RA tapering and discontinuation in patients with ITP. Using a modified Delphi panel approach, ITP experts developed consensus statements regarding the use of TPO-RA tapering and discontinuation. RESULTS: Survey respondents estimated that 30-34% of their patients were suitable for tapering or discontinuation and that 29-35% of these patients required treatment re-initiation after an average treatment-free interval of 86-106 days. No clear predictors of patient suitability or response to tapering or discontinuation were identified. The ITP expert consensus was that approximately 30% of patients are eligible for tapering and discontinuation, which may be considered after 6-12 months for patients demonstrating an adequate treatment response (platelet count >50,000/µL at ≥75% of assessments in the preceding 6 months). Treatment re-initiation may be considered if the platelet count decreases or if the patient becomes symptomatic. Individual differences need to be taken into account when considering TPO-RA tapering or discontinuation. CONCLUSIONS: Tapering and discontinuation of TPO-RA therapy may be considered for certain patients with ITP. Further study is needed to better predict patients likely to achieve sustained off-treatment responses after tapering and discontinuation.

Thrombopoetin receptor agonist therapy in thrombocytopenia: ITP and beyond.

Eltrombopag is well established in treatment of severe immune thrombocytopenia (ITP) and is increasingly commonplace in second-line management. A role is also suggested for both bridging therapy for surgery, as well as treating thrombocytopenia due to non-immune aetiologies. We present the largest single-centre experience with eltrombopag, with our cohort of 62 patients. Patients with severe ITP (n = 34) had 91·2% response, which was sustained over a median of 18·5 months. In 41·4% of ITP cases (n = 14), complete response (CR- platelet count >100 × 109 /l) was achieved and in 2 cases, therapy was stopped and CR maintained. In our bridging group (n = 15) with a higher baseline platelet count, 93·3% achieved a CR. In the non-ITP group (n = 13), a response was achieved in 76·9%. In all groups, side effects were transient, with the drug discontinued in 2 patients due to minor complications (rash, nausea, diarrhoea). We conclude that eltrombopag is both effective and well tolerated as therapy in severe ITP. It is also advantageous in ITP patients who do not normally require therapy, but need a temporary platelet count boost pre-procedure. Furthermore, there are potentially far wider implications for the use of eltrombopag in counteracting thrombocytopenia beyond ITP, which merit further investigation.

A single-center prospective study on the safety of plasma exchange procedures using a double-viral-inactivated and prion-reduced solvent/detergent fresh-frozen plasma as the replacement fluid in the treatment of thrombotic microangiopathy.

BACKGROUND: Patients presenting with acute episodes of thrombotic microangiopathies (TMAs) require urgent access to plasma exchange (PEX). OctaplasLG, a solvent/detergent fresh-frozen plasma product that has undergone viral inactivation and prion reduction step, has been used in our institution since 2013, replacing Octaplas. STUDY DESIGN AND METHODS: We prospectively reviewed 981 PEX procedures where OctaplasLG was the replacement fluid in 90 patients admitted acutely with a TMA presentation within our institution from January 1, 2013, to December 31, 2015. We recorded citrate toxicities, plasma reactions, viral transfer, complications related to central venous catheter, and venous thrombotic events (VTEs). RESULTS: Citrate toxicities were 5.4%, plasma reactions were 2%, and all were classified as Grade 1 or 2. VTE had an incidence of 12.2%, although 50% of the episodes occurred in early remission when patients were not receiving PEX. No line insertions complications were recorded. Line-associated infections were 2.2%. Hepatitis B and C serology and human immunodeficiency virus (HIV) were checked on admission. There were four patients who may have had passive transient transfer of hepatitis B antibodies from pooled plasma. No hepatitis C or HIV viral transfer was documented after treatment and no seroconversion was detected after treatment. CONCLUSION: Our data have demonstrated that the incidence of complications during PEX is low and using OctaplasLG is comparable to the low incidence of reactions. No cases of anaphylaxis, transfusion-related acute lung injury, or fatal plasma reactions were seen. There was no evidence of viral transmission or seroconversion after treatment.

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura.

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody-mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)-2, IL-4, IL-6, IL-10, tumour necrosis factor, interferon-γ and IL-17a) were measured in 20 acute TTP patients and 49 remission cases. Anti-ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL-6 and IL-10 levels were significantly higher in the acute vs. remission groups, IL-6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL-10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti-ADAMTS13 IgG (rs = 0·604, P = 0·017) and IL-10 (rs = 0·692, P = 0·006). No anti-ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti-ADAMTS13 IgG antibody and IL-10 levels.