Distinguishing ASH Clinical Practice Guidelines from Other Forms of ASH Clinical Advice.

The American Society of Hematology (ASH) develops a variety of resources that provide guidance to clinicians on the diagnosis and management of blood diseases. These resources include clinical practice guidelines (CPGs) and other forms of clinical advice. While both ASH CPGs and other forms of clinical advice provide recommendations, they differ with respect to the methods underpinning their development, the principal type of recommendations they offer, their transparency and concordance with published evidence, and the time and resources required for their development. It is crucial that end users be aware of the differences between CPGs and other forms of clinical advice and that producers and publishers of these resources use clear and unambiguous terminology to facilitate their distinction. The objective of this article is to highlight similarities and differences between ASH CPGs and other forms of ASH clinical advice and to discuss the implications of these differences for end users.

Thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced immune thrombocytopenia and thrombosis (VITT): Brighton Collaboration case definitions and guidelines for data collection, analysis, and presentation of immunisation safety data.

This is a revision of the online November 2021 Brighton thrombosis with thrombocytopenia syndrome (TTS) case definition and a new Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis (VITT). These case definitions are intended for use in clinical trials and post-licensure pharmacovigilance activities to facilitate safety data comparability across multiple settings. They are not intended to guide clinical management. The case definitions were developed by a group of subject matter and Brighton Collaboration process experts as part of the Coalition for Epidemic Preparedness Innovations (CEPI)-funded Safety Platform for Evaluation of vACcines (SPEAC). The case definitions, each with defined levels of diagnostic certainty, are based on relevant published evidence and expert consensus and are accompanied by specific guidelines for TTS and VITT data collection and analysis. The document underwent peer review by a reference group of vaccine safety stakeholders and haematology experts to ensure case definition useability, applicability and scientific integrity.

Acute aortic intraluminal thrombus with embolisation and lower-limb ischaemia following intravenous iron sucrose infusion reaction.

A woman in her 50s developed iron deficiency anaemia. Her medical history included hypertension, asthma and remote postpartum pulmonary embolism. There was a strong family history of atherosclerosis. After receiving intravenous iron sucrose (500 mg), she developed vomiting and large-volume diarrhoea, followed by diaphoresis, back pain, haemoconcentration (haematocrit increase, 0.242 to 0.326), leucocytosis and platelet count decline. Myocardial infarction was ruled out and the truncal pain subsided. However, 2 days postdischarge, she was diagnosed with aortic intraluminal thrombus (ILT) with embolisation into the lower extremities. The limbs were salvaged by emergency embolectomies and fasciotomies. Acute aortic ILT is a rare disorder that has not been previously reported as a complication of parenteral iron therapy. We postulate that acute intravascular volume losses (vomiting and diarrhoea) with resulting haemoconcentration and catecholamine-associated platelet activation and consumption, in a patient with subclinical aortic atherosclerosis, triggered acute aortic ILT presenting as lower-limb ischaemia.

Impact of iron supplementation on patient outcomes for women with abnormal uterine bleeding: a protocol for a systematic review and meta-analysis.

BACKGROUND: Abnormal uterine bleeding (AUB), which includes heavy menstrual bleeding (HMB), is a common condition placing women at increased risk for developing iron deficiency and iron deficiency anemia (IDA). Depletion of iron stores has negative implications on physical, social, and emotional health, as well as quality of life. Iron supplements are safe, effective, and readily available, while red blood cell (RBC) transfusions have inherent risks including infectious and immune reactions. Despite high prevalence of IDA among women with AUB, there are limited studies on the impact of iron therapies on patient outcomes. This systematic review and meta-analysis will evaluate the impact of iron supplementation on patient outcomes for women with AUB, when compared to combination therapy, no intervention, placebo, or standard of care. METHODS: We will conduct a systematic review and meta-analysis of randomized controlled trials and observational studies evaluating the impact of iron interventions on patient outcomes for women with AUB. Systematic literature searches will be conducted in major databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science. Studies assessing the impact of iron interventions on patient outcomes in women experiencing AUB, in comparison to combination therapy, no intervention, placebo, or standard of care, will be included in the review. Independent reviewers will screen for eligibility, assess risk of bias, and abstract data. Overall certainty of evidence for each outcome will be assessed using the GRADE approach. We will meta-analyze outcomes which are sufficiently homogeneous to summarize intervention effects and narratively synthesize nonhomogeneous outcomes. The main outcomes of interest are hemoglobin levels immediately prior to surgery and post-operatively, number of RBC transfusions, and adverse effects. Secondary outcomes will include length of hospital stay, intraoperative blood loss, adverse and side effects, quality of life, and iron indices. DISCUSSION: This review will evaluate the impact of iron interventions on patient outcomes in women with IDA secondary to AUB with focus on changes in hematological and iron indices, red blood cell utilization, quality of life, cost of treatment, and adverse events. The results will inform evidence-based clinical practice for the management of iron deficiency and IDA secondary to AUB. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137282.

Defining ferritin clinical decision limits to improve diagnosis and treatment of iron deficiency: A modified Delphi study.

BACKGROUND: Iron deficiency is highly prevalent worldwide and is an issue of health inequity. Despite its high prevalence, uncertainty on the clinical applicability and evidence-base of iron-related lab test cut-offs remains. In particular, current ferritin decision limits for the diagnosis of iron deficiency may not be clinically appropriate nor scientifically grounded. METHODS: A modified Delphi study was conducted with various clinical experts who manage iron deficiency across Canada. Statements about ferritin decision limits were generated by a steering committee, then distributed to the expert panel to vote on agreement with the aim of achieving consensus and acquiring feedback on the presented statements. Consensus was reached after two rounds, which was defined as 70% of experts rating their agreement for a statement as 5 or higher on a Likert scale from 1 to 7. RESULTS: Twenty-six clinical experts across 10 different specialties took part in the study. Consensus was achieved on 28 ferritin decision limit statements in various populations (including patients with multiple comorbid conditions, pediatric patients, and pregnant patients). For example, there was consensus that a ferritin <30 µg/L rules in iron deficiency in all adult patients (age ≥ 18 years) and warrants iron replacement therapy. CONCLUSION: Consensus statements generated through this study corresponded with current evidence-based literature and guidelines. These statements provide clarity to facilitate clinical decisions around the appropriate detection and management of iron deficiency.

Epidemiology of VITT.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a life-threatening syndrome of aggressive thrombosis, often profound thrombocytopenia, and frequently overt disseminated intravascular coagulation. It has been associated with 2 adenovirus vector COVID-19 vaccines: ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen). Unlike the myriad of other conditions that cause thrombosis and thrombocytopenia, VITT has an important distinguishing feature: affected individuals have platelet activating anti-PF4 antibodies that appear in a predictable time frame following vaccination. The reported incidence of VITT differs between jurisdictions; it is dependent on accurate ascertainment of cases and accurate estimates of the size of the vaccinated population. The incidence ranges from 1 case per 26,500 to 127,3000 first doses of ChAdOx1 nCoV-19 administered. It is estimated at 1 case per 518,181 second doses of ChAdOx1 nCoV-19 administered, and 1 case per 263,000 Ad26.COV2.S doses administered. There are no clear risk factors for VITT, including sex, age, or comorbidities. VITT is a rare event, but its considerable morbidity and mortality merit ongoing pharmacovigilance, and accurate case ascertainment.

Vaccine-induced immune thrombotic thrombocytopenia (VITT): Update on diagnosis and management considering different resources.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe immunological reaction to the non-replicable adenoviral vector-based COVID-19 vaccines. Extreme activation of platelets and the coagulation system leads to a high risk of death from venous or arterial thrombosis or secondary hemorrhage. Public and clinician awareness has reduced mortality of VITT by nearly 90%. The World Health Organization provided a guideline in July 2021 on diagnosis and management of VITT (also called thrombosis with thrombocytopenia syndrome, or TTS). Since July 2021, new, clinically relevant information has become available. This update has been summarized by the authors in an informal process with recommendations for low resource environments. We provide new available evidence on VITT to empower clinicians to recognize VITT early, then effectively diagnose and treat the disorder to reduce morbidity and mortality. We strongly encourage production of clear management pathways for primary care settings and hospital settings.

Vaccine-induced immune thrombotic thrombocytopenia.

In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca-Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.

Background incidence rates of hospitalisations and emergency department visits for thromboembolic and coagulation disorders in Ontario, Canada for COVID-19 vaccine safety assessment: a population-based retrospective observational study.

OBJECTIVE: The objective of this study was to estimate background rates of selected thromboembolic and coagulation disorders in Ontario, Canada. DESIGN: Population-based retrospective observational study using linked health administrative databases. Records of hospitalisations and emergency department visits were searched to identify cases using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada diagnostic codes. PARTICIPANTS: All Ontario residents. PRIMARY OUTCOME MEASURES: Incidence rates of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, deep vein thrombosis, pulmonary embolism, idiopathic thrombocytopaenia, disseminated intravascular coagulation and cerebral venous thrombosis during five prepandemic years (2015-2019) and 2020. RESULTS: The average annual population was 14 million with 51% female. The mean annual rates per 100 000 population during 2015-2019 were 127.1 (95% CI 126.2 to 127.9) for ischaemic stroke, 22.0 (95% CI 21.6 to 22.3) for intracerebral haemorrhage, 9.4 (95% CI 9.2 to 9.7) for subarachnoid haemorrhage, 86.8 (95% CI 86.1 to 87.5) for deep vein thrombosis, 63.7 (95% CI 63.1 to 64.3) for pulmonary embolism, 6.1 (95% CI 5.9 to 6.3) for idiopathic thrombocytopaenia, 1.6 (95% CI 1.5 to 1.7) for disseminated intravascular coagulation, and 1.5 (95% CI 1.4 to 1.6) for cerebral venous thrombosis. Rates were lower in 2020 than during the prepandemic years for ischaemic stroke, deep vein thrombosis and idiopathic thrombocytopaenia. Rates were generally consistent over time, except for pulmonary embolism, which increased from 57.1 to 68.5 per 100 000 between 2015 and 2019. Rates were higher for females than males for subarachnoid haemorrhage, pulmonary embolism and cerebral venous thrombosis, and vice versa for ischaemic stroke and intracerebral haemorrhage. Rates increased with age for most of these conditions, but idiopathic thrombocytopaenia demonstrated a bimodal distribution with incidence peaks at 0-19 years and ≥60 years. CONCLUSIONS: Our estimated background rates help contextualise observed events of these potential adverse events of special interest and to detect potential safety signals related to COVID-19 vaccines.

Vaccine-induced immune thrombotic thrombocytopenia presenting with normal platelet count.

Adenoviral-vector based vaccines for coronavirus disease 2019 (COVID-19) have been linked with a thrombotic syndrome, vaccine-induced thrombotic thrombocytopenia (VITT). A key clinical question is whether VITT can be reliably ruled out by the absence of thrombocytopenia. We report on three patients who presented to our institute with this syndrome. Noteworthy in our presentations are two patients who presented for medical assessment of thrombotic symptoms with a normal platelet count, one preceding and one following a period of thrombocytopenia. Prompt diagnosis of VITT is critical to prevent rapid patient decline. We provide herein a new diagnostic algorithm that we believe will help optimally capture case presentations of VITT. These cases broaden and refine our understanding of the disease process and highlight to practitioners that VITT cannot be adequately ruled out by thrombocytopenia alone.

Acquired Hemophilia A.

Acquired hemophilia A is a potentially severe bleeding disorder caused by antibodies against the patient's own factor VIII. Acquired hemophilia A is rare. It is most commonly diagnosed in older individuals; about one-half of cases of acquired hemophilia are associated with underlying conditions, including autoimmune disease, cancer, and pregnancy. The diagnosis of acquired hemophilia A can be suspect with an isolated activated partial thromboplastin time elevation, and confirmed with demonstration of reduced factor VIII activity and the presence of a specific factor VIII inhibitor. Treatment of acquired hemophilia A involves control of bleeding, and eradication of the inhibitor.