Blood-brain barrier permeability in survivors of immune-mediated thrombotic thrombocytopenic purpura: A pilot study

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity, 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) 3 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of 20.312 mL/min/100 g (95% confidence interval: 20.4729 to 20.1510; P 5.0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. Summary: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic\ue2\u80\u93uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic Microangiopathy is a broad pathophysiological process that leads to microangiopathic hemolytic anemia, thrombocytopenia and involves capillary and small vessel platelet aggregates. The most common cause being disseminated intravascular coagulation (DIC), which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia (MAHAT), including cancer, infection, transplantation, drugs, autoimmune disease and pre-eclampsia and HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiology and treatment pathways. OBJECTIVES Presented is a consensus document from an international working group on TTP and associated TMAs (thrombotic microangiopathies). METHODS The international working group has proposed definitions and terminology based on published information and consensus based recommendations. CONCLUSION The consensus aims to aid clinical decisions but also future studies and trials, utilizing standardized definitions. It presents classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune mediated TTP. This article is protected by copyright. All rights reserved

Development of a national out-of-hospital transfusion protocol: a modified RAND Delphi study

Background: Early resuscitation with blood components or products is emerging as best practice in selected patients with trauma and medical patients; as a result, out-of-hospital transfusion (OHT) programs are being developed based on limited and often conflicting evidence. This study aimed to provide guidance to Canadian critical care transport organizations on the development of OHT protocols. Methods: The study period was July 2021 to June 2022. We used a modified RAND Delphi process to achieve consensus on statements created by the study team guiding various aspects of OHT in the context of critical care transport. Purposive sampling ensured representative distribution of participants in regard to geography and relevant clinical specialties. We conducted 2 written survey Delphi rounds, followed by a virtual panel discussion (round 3). Consensus was defined as a median score of at least 6 on a Likert scale ranging from 1 (“Definitely should not include”) to 7 (“Definitely should include”). Statements that did not achieve consensus in the first 2 rounds were discussed and voted on during the panel discussion. Results: Seventeen subject experts participated in the study, all of whom completed the 3 Delphi rounds. After the study process was completed, a total of 39 statements were agreed on, covering the following domains: general oversight and clinical governance, storage and transport of blood components and products, initiation of OHT, types of blood components and products, delivery and monitoring of OHT, indications for and use of hemostatic adjuncts, and resuscitation targets of OHT. Interpretation: This expert consensus document provides guidance on OHT best practices. The consensus statements should support efficient and safe OHT in national and international critical care transport programs. The transfusion of blood components such as red blood cells (RBCs) and plasma is increasingly common in prehospital and transport medicine.1–3 In addition, the potential benefits of out-of-hospital administration of whole blood or blood products such as fibrinogen and prothrombin complex concentrate in selected patients are being investigated. In this report, we use the umbrella term “out-of-hospital transfusion” (OHT) to refer to the transfusion of whole blood, blood components such as RBCs and plasma, or blood products such as fibrinogen and prothrombin complex concentrate. Although the increasing practice of OHT suggests general consensus on a likely clinical benefit, evidence regarding the effect of OHT on morbidity and mortality is limited and conflicting.2,4–6 The generalizability of the limited evidence is further complicated in that the feasibility and potential benefit of OHT are dependent on multiple regional factors such as geography, patient factors and health care configuration. For example, 2 secondary analyses of the data sets from the Prehospital Air Medical Plasma (PAMPer) and the Control of Major Bleeding After Trauma (COMBAT) clinical trials suggested that OHT was beneficial if transport times were greater than 20 minutes and that a benefit present in blunt trauma does not translate to a benefit in penetrating trauma.7,8 In addition, out-of-hospital management of acute hemorrhage extends beyond OHT and includes factors such as administration of tranexamic acid, avoidance of hypothermia and physical means of hemorrhage control where possible.9,10 Efficient and effective implementation of OHT requires a combination of medical and logistic considerations that span multiple specialties. This is particularly relevant in countries like Canada, with long transport times to tertiary care centres, and remote communities that have limited or no access to physicians or blood components and products at their local health care facilities.11 We invited an expert panel to provide expert opinions on out-of-hospital hemorrhage management and, in particular, OHT to develop national consensus recommendations to guide OHT practice and to begin to optimize the effectiveness and safety of OHT

Human Leukocyte Antigen Alloimmunization and Alloimmune Platelet Refractoriness

Despite significant advancements in the production of platelet products, storage, and transfusion, transfusion refractoriness remains a significant clinical problem, affecting up to 14% of hematological patients receiving platelet transfusions. Human leukocyte antigen (HLA) alloimmunization is a major cause of immune platelet refractoriness, and its rate can be significantly reduced by implementation of leukoreduction. Despite promising preclinical results, pathogen reduction does not reduce HLA alloimmunization. Patients with HLA alloimmune refractoriness are usually managed with HLA-selected platelet transfusions. In this review, we describe the pathophysiology of HLA alloimmunization and alloimmune refractoriness, as well as options to prevent and treat these transfusion complications. We discuss the evidence supporting these options and point out the outstanding gaps. Finally, we review the possible future directions for prevention and treatment of alloimmune refractoriness

Management of immune thrombotic thrombocytopenic purpura with caplacizumab: a Canadian, single-centre, real-world experience

When combined with therapeutic plasma exchange (TPE) and immunosuppression, upfront universal administration of caplacizumab was shown to be effective in the management of immune thrombotic thrombocytopenic purpura (iTTP). However, access to this drug remains challenging in many jurisdictions. We retrospectively review results of a single-institution experience with caplacizumab over a 3-year period. During the study period, we treated 48 patients with iTTP, of which 11 (23%) received caplacizumab. Eight of these 11 patients (73%) were female; the median age was 45 years (IQR 37.0–58.5). All received TPE within 24 h of admission (median 9 exchanges, IQR 7.0–12.5), and high-dose steroids. Caplacizumab was initiated for a median of 6 days after admission (IQR 2.5–8.0) and continued for a median of 26 days (IQR 14.0–33.0). Five patients (45%) had refractory disease at caplacizumab initiation. Ten patients (91%) survived, reaching clinical remission. Platelet normalization was reached with a median of 4 days following caplacizumab initiation (IQR 1.5–4.0). Complications included minor bleeding (n = 1) and local allergic reaction (n = 1). No patients experienced TTP exacerbation; relapse occurred in two patients (18%) over 1–5 years of follow-up. Caplacizumab appeared to be effective and safe, despite delayed initiation and in the setting of refractory disease

Patient Education on Pre-operative Anemia: Using Character Animation to Promote Patient Activation

Preoperative anemia affects up to 76% of the surgical population. One of the strongest predictors of allogenic blood transfusions (ABT), preoperative anemia is associated with worse patient outcomes including post-operative morbidity and mortality. Patient blood management (PBM) is a multidisciplinary program developed to address preoperative anemia and prevent unnecessary transfusions. Though PBM has been shown to reduce ABT and improve patient outcomes, many barriers to PBM implementation exist. Among these is patients’ lack of awareness and insufficient patient-centered educational resources that could improve patient activation.Previous studies suggest that character-driven stories are especially effective in sign-posting access to health resources among different demographics. However, due to production limitations and adherence to current motion graphic trends (e.g., whiteboard animation and text animation), character-driven stories tend to be neglected in patient education. We propose to develop a patient education animation focused on three representative preoperative anemia patients.  The narrative follows the characters’ health journeys from diagnosis to treatment, as we use a combination of 2D and 3D character animation, motion graphics, and data visualization to clarify some of the most common misconceptions and knowledge gaps around pre-operative anemia. We aim for the animation to achieve two main communication goals: 1) to educate all preoperative patients on the risk and benefits of blood transfusion; and 2) to improve public awareness of the Patient Blood Management Program (PBM), thereby increasing patient activation and enhancing preoperative care outcomes.Upon completion, this project will be the first character-driven educational animation addressing PBM. Evaluation of this project will provide further evidence of the effectiveness of character-driven storytelling in inspiring patient activation, which will enable more biomedical communicators to produce better patient-education resources