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

Use of Intravenous Albumin:A Guideline From the International Collaboration for Transfusion Medicine Guidelines

Background: Albumin is used commonly across a wide range of clinical settings to improve hemodynamics, to facilitate fluid removal, and to manage complications of cirrhosis. The International Collaboration for Transfusion Medicine Guidelines developed guidelines for the use of albumin in patients requiring critical care, undergoing cardiovascular surgery, undergoing kidney replacement therapy, or experiencing complications of cirrhosis. Study Design and Methods: Cochairs oversaw the guideline development process and the panel included researchers, clinicians, methodologists, and a patient representative. The evidence informing this guideline arises from a systematic review of randomized clinical trials and systematic reviews, in which multiple databases were searched (inception through November 23, 2022). The panel reviewed the data and formulated the guideline recommendations using Grading of Recommendations Assessment, Development, and Evaluation methodology. The guidelines were revised after public consultation. Results: The panel made 14 recommendations on albumin use in adult critical care (three recommendations), pediatric critical care (one recommendation), neonatal critical care (two recommendations), cardiovascular surgery (two recommendations), kidney replacement therapy (one recommendation), and complications of cirrhosis (five recommendations). Of the 14 recommendations, two recommendations had moderate certainty of evidence, five recommendations had low certainty of evidence, and seven recommendations had very low certainty of evidence. Two of the 14 recommendations suggested conditional use of albumin for patients with cirrhosis undergoing large-volume paracentesis or with spontaneous bacterial peritonitis. Twelve of 14 recommendations did not suggest albumin use in a wide variety of clinical situations where albumin commonly is transfused. Interpretation: Currently, few evidence-based indications support the routine use of albumin in clinical practice to improve patient outcomes. These guidelines provide clinicians with actionable recommendations on the use of albumin.</p

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

New mutation found to cause hereditary thrombotic thrombocytopenic purpura in a patient presenting with seizures in adulthood

We present a case of hereditary thrombotic thrombocytopenic purpura (hTTP) caused by a previously undescribed mutation in a 36-year-old woman who presented with seizures in the context of a possible infection. Her hematologic manifestations were mild, despite undetectable ADAMTS13 (A Distintegrin and Metalloproteinase with Thrombospondin Motifs 13) activity. Genetic analysis showed a homozygous variant in ADAMTS13 gene which was not previously reported but predicted to be associated with disease. She responded to plasma therapy. Her diagnosis subsequently led to the diagnosis of hTTP in her younger sibling who presented with unexplained strokes a few years earlier

Bleeding complications from the direct oral anticoagulants

Abstract Background Direct oral anticoagulants (DOACs) are now standard of care for the management of thromboembolic risk. A prevalent issue of concern is how to manage direct oral anticoagulant (DOAC)-associated bleeding for which there is no specific antidote available for clinical use. We conducted a retrospective case series to describe the Toronto, Canada multicenter experience with bleeding from dabigatran or rivaroxaban. Methods Retrospective chart review of DOAC bleeding necessitating referral to hematology and/or transfusion medicine services at five large University of Toronto affiliated academic hospitals from January 2011 to December 2013. Results Twenty-six patients with DOAC bleeding were reviewed; 42 % bleeds intracranial and 50 %, gastrointestinal. All patients had at least one risk factor associated with DOAC bleeding reported in previous studies. Inconsistent bleed management strategies were evident. Median length of hospital stay was 11 days (1–90). Five thromboembolic events occurred after transfusion based-hemostatic therapy and there were six deaths. Conclusions Management of DOAC bleeding is variable. Clinical trial data regarding DOAC reversal is needed to facilitate optimization and standardization of bleeding treatment algorithms