High prevalence of iron deficiency and socioeconomic disparities in laboratory screening of non-pregnant females of reproductive age: A retrospective cohort study.

Iron deficiency anemia (IDA) and non-anemic iron deficiency (NAID) are highly prevalent among non-pregnant females of reproductive age. Canada has no national screening guidelines for this population. Screening, when performed, is often with a complete blood count alone without ferritin or iron indices. The primary objective was to determine the prevalence of screening for NAID and IDA over a 3-year period in non-pregnant females of reproductive age who had tests performed at outpatient laboratories in Ontario, Canada. Retrospective cohort study of non-pregnant females ages 15-54 in Ontario, from 2017 to 2019. NAID was defined as ferritin <30 µg/L, anemia as hemoglobin <120 g/L, and IDA as ferritin <30 µg/L and hemoglobin <120 g/L. Annual household income was estimated using patient postal codes. A total of 784 132 non-pregnant females were included. The 82.1% were screened for iron deficiency, 38.3% had NAID and 13.1% had IDA; 55.6% with IDA had normal mean corpuscular volumes. The median household income was $89454.80 compared with a provincial median of $65285.00. Patients in the lowest income quintile had the highest odds of being anemic, and the lowest odds of having a ferritin checked. A large proportion of non-pregnant females of reproductive age in this cohort were screened for iron deficiency. In this relatively privileged cohort, NAID affected nearly 40%, and IDA 13%. Most patients with IDA did not have microcytosis. Low household income was associated with the greatest odds of anemia and the lowest odds of being screened, highlighting inequitable access to screening for IDA in Ontario, Canada.

Tranexamic acid for management of heavy vaginal bleeding: barriers to access and myths surrounding its use.

Tranexamic acid is safe and effective for the treatment of heavy vaginal bleeding during menstruation and childbirth. It improves the quality of life, facilitates participation in school and work, and reduces the risk of death from postpartum hemorrhage. Despite its well-established benefits, individual- and structural-level barriers preclude its widespread utilization, hindering effective patient care and perpetuating health inequities in women's health. We first describe the evidence for the use of tranexamic acid in treating heavy menstrual bleeding and postpartum hemorrhage. Barriers to tranexamic acid use, including structural sexism, period poverty, misinformation in product monograph labeling, stigmatization of vaginal blood loss, and drug access, are then discussed. Finally, we summarize relevant data presented during the 2023 International Society on Thrombosis and Haemostasis Congress.

Management of coagulopathy among patients with cirrhosis undergoing upper endoscopy and paracentesis: Persistent gaps and areas of consensus in a multispecialty Delphi.

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of 286 possible measures, 33 measures made the final set. International normalized ratio testing was not required for diagnostic or therapeutic paracentesis as well as diagnostic endoscopy. Plasma transfusion should be avoided for all paracenteses and diagnostic endoscopy. No consensus was achieved for these items in therapeutic intent or emergent endoscopy. The risks of prophylactic platelet transfusions exceed their benefits for outpatient diagnostic paracentesis and diagnostic endosopies. For the other procedures examined, the risks outweigh benefits when platelet count is >20,000/mm 3 . It is uncertain whether risks outweigh benefits below 20,000/mm 3 in other contexts. No consensus was achieved on whether it was permissible to continue or stop systemic anticoagulation. Continuous aspirin was permissible for each procedure. Clopidogrel was permissible for diagnostic and therapeutic paracentesis and diagnostic endoscopy. We found many areas of consensus that may serve as a foundation for a common set of practice metrics for the periprocedural management of coagulopathy in cirrhosis.

2023 ISTH update of the 2022 ISTH guidelines for antithrombotic treatment in COVID-19.

Based on emerging evidence from the COVID-19 pandemic, the International Society on Thrombosis and Haemostasis (ISTH) guidelines for antithrombotic treatment in COVID-19 were published in 2022. Since then, at least 16 new randomized controlled trials have contributed additional evidence, which necessitated a modification of most of the previous recommendations. We used again the American College of Cardiology Foundation/American Heart Association methodology for assessment of level of evidence (LOE) and class of recommendation (COR). Five recommendations had the LOE upgraded to A and 2 new recommendations on antithrombotic treatment for patients with COVID-19 were added. Furthermore, a section was added to answer questions about COVID-19 vaccination and vaccine-induced immune thrombotic thrombocytopenia (VITT), for which studies have provided some evidence. We only included recommendations with LOE A or B. Panelists agreed on 19 recommendations, 4 for nonhospitalized, 5 for noncritically ill hospitalized, 3 for critically ill hospitalized, and 2 for postdischarge patients, as well as 5 for vaccination and VITT. A strong recommendation (COR 1) was given for (a) use of prophylactic dose of low-molecular-weight heparin or unfractionated heparin in noncritically ill patients hospitalized for COVID-19, (b) for select patients in this group, use of therapeutic-dose low-molecular-weight heparin/unfractionated heparin in preference to prophylactic dose, and (c) for use of antiplatelet factor 4 enzyme immunoassays for diagnosing VITT. A strong recommendation was given against (COR 3) the addition of an antiplatelet agent in hospitalized, noncritically ill patients. These international guidelines provide recommendations for countries with diverse healthcare resources and COVID-19 vaccine availability.

Thrombopoietin Receptor Agonists and Other Second-Line Therapies for Immune Thrombocytopenia: A Narrative Review With a Focus on Drug Access in Canada.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP.

ABSTRACT: Fc gamma receptor (FcγR) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). FcγRIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of FcγRIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of FcγRIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody's Fc and/or bivalent nature. The blockade of human FcγRIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block FcγRIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human FcγRIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum-sensitized human platelets. In vivo studies using FcγR-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human FcγRIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.

Iron deficiency anemia among women: An issue of health equity.

Iron deficiency is the most common and widespread nutritional deficiency in the world. For women, the risk of iron deficiency and iron deficiency anemia increases due to iron demands during pregnancy and regular iron losses due to menstruation during reproductive years. These interrelated conditions are of public health concern as they are highly prevalent, and the negative consequences such as chronic fatigue, cognitive impairment and poor quality of life are broad and multifaceted. People of low socioeconomic status are at higher risk of iron deficiency due to low intake of expensive iron-rich foods, and decreased access to healthcare. In this review, we applied a health equity lens to describe the current state of care for women with iron deficiency with or without anemia. We have highlighted several structural challenges that span from the laboratory diagnosis, inconsistent screening guidelines, and stigma associated with heavy menstrual bleeding, to treatment barriers.

Iron Surveillance and Management in Gastro-Intestinal Oncology Patients: A National Physician Survey.

PURPOSE: Iron deficiency (ID) is a complication of gastrointestinal (GI) cancers that may manifest as iron deficiency anemia (IDA). Serum ferritin monitoring and oral iron supplementation have the limitations of being falsely elevated and poorly absorbed, respectively. This study aims to assess the discordance in surveillance, treatment practices, and awareness of ID/IDA in GI cancer patients by Canadian physicians treating these patients. METHODS: From February 2020 to September 2021, a 22-question electronic survey was sent to medical oncologists (MOs), surgical oncologists (SOs), and gastroenterologists (GEs). The survey collected information about four domains: physician demographics, surveillance practices, treatment practices, and awareness of ID/IDA in GI cancer patients and ASCO/ASH guidelines. RESULTS: A total of 108 (34 MOs, 19 SOs, and 55 GEs) of the 872 (12.4%) invited physicians completed the survey. Of these, 26.5% of MOs, 36.8% of SOs, and 70.9% of GEs measured baseline iron parameters, with few continuing surveillance throughout treatment. Ferritin was widely measured by MOs (88.9%), SOs (100%), and GEs (91.4%). Iron was supplemented if ID/IDA was identified pre-treatment by 66.7% of MOs, 85.7% of SOs, and 94.2% of GEs. Parenteral iron was prescribed by SOs (100%), while oral iron was prescribed by MOs (83.3%) and GEs (87.9%). Only 18.6% of physicians were aware of the ASCO/ASH guidelines regarding erythropoiesis-stimulating agents with parenteral iron for treating chemotherapy-induced anemia. CONCLUSION: Results illustrate variations in practice patterns for IDA management across the different physician specialties. Moreover, there appeared to be gaps in the knowledge and care surrounding evidence-based IDA management principles which may contribute to poor clinical outcomes.

Identification of women and girls with iron deficiency in the reproductive years.

Iron deficiency (ID) is the most common micronutrient deficiency in the world. It is of concern for women and girls of reproductive age as, despite frequent normalization, excessive menstrual blood loss and the iron demands associated with pregnancy increase the risk of developing an ID. Iron deficiency reduces health-related quality of life with symptoms of fatigue, heart palpitations, difficulty concentrating, and poor mental health. When left untreated, ID can escalate to iron deficiency anemia (IDA), where there is an insufficiency of red blood cells, or hemoglobin within these cells, to meet the bodily demands for oxygen transport. Substantial guidance on screening for ID can be found in specific at-risk groups, including pregnant women and patients with renal, cardiac, and inflammatory bowel disease. However, it was unclear whether guidance is available for women of reproductive age. We performed a literature search to explore the current recommendations for screening women of reproductive age for ID. While four manuscripts supportive of screening were found, no official guidance appears to exist regarding screening for this group. In line with the World Health Organization's 10 Principles of Screening, we present a case for ID screening in women and girls of reproductive age.

Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) took place in person in Montréal, Canada, from June 24-28, 2023. The conference, held annually, highlighted cutting-edge advances in basic, translational, population and clinical sciences relevant to the Society. As for all ISTH congresses, we offered a special, congress-specific scientific theme; this year, the special theme was immunothrombosis. Certainly, over the last few years, COVID-19 infection and its related thrombotic and other complications have renewed interest in the concepts of thromboinflammation and immunothrombosis; namely, the relationship between inflammation, infection and clotting. Other main scientific themes of the Congress included Arterial Thromboembolism, Coagulation and Natural Anticoagulants, Diagnostics and Omics, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostatic System in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. Among other sessions, the program included 28 State-of-the-Art (SOA) sessions with a total of 84 talks given by internationally recognized leaders in the field. SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the Congress.

Patient-centered care in von Willebrand disease: are we there yet?

INTRODUCTION: Von Willebrand Disease is the most common inherited bleeding disorder. Paradoxically, affected individuals are often misdiagnosed and experience substantial diagnostic delay. There are sex-specific health disparities in VWD rooted in the stigmatization of vaginal bleeding, which leads to symptom dismissal, lack of timely access to care and lower health-related quality of life. AREAS COVERED: Following the core elements of patient-centered care - respect for patient preferences, values, and needs, we describe the current state of VWD care. Challenges of diagnostic delay, serial misrecognition of abnormal bleeding, and symptom dismissal are barriers that disproportionately affect women with VWD. These negative effects are further amplified in individuals living in low- and middle-income countries. We describe the importance of coordinated multidisciplinary care, as well as the need for patient education and empowered self-advocacy. EXPERT OPINION: While tremendous work has been done to improve the diagnosis and management of VWD, timely and high-quality research is urgently needed to address care gaps. Systemic changes such as resource investment, dedicated research funding for novel treatment modalities, and effective knowledge translation strategies to address structural barriers are needed to facilitate effective patient-centered care for VWD.

Evaluation of the association of factor XIII at hospital arrival and outcomes in a cohort of severely injured patients.

BACKGROUND: Severe traumatic bleeding depletes coagulation factor XIII (FXIII) and fibrinogen. However, the role of FXIII level in bleeding-related outcomes is unknown. OBJECTIVES: To evaluate the association between FXIII levels at hospital arrival and critical administration threshold (≥3 red blood cell units in 1 hour within the first 24 hours), bleeding-related outcomes, death, and baseline characteristics. METHODS: A retrospective cohort study was conducted in severely injured adult patients (Injury Severity Score of ≥22 or ≥2 red blood cell units transfused in 24 hours) admitted to a level 1 trauma center. Clinical and laboratory data were collected. Baseline FXIII antigen levels were measured in banked patient plasma. Multivariable logistic and linear regression models were used to estimate the association between FXIII levels, outcomes, and baseline characteristics. RESULTS: Three hundred sixty-four of 1730 subjects admitted during a 2-year period were analyzed. Median age was 44 years (IQR, 27-62 years), and median Injury Severity Score was 29 (IQR, 22-34). FXIII levels were not associated with critical administration threshold (odds ratio [OR], 1.06; 95% CI, 0.97-1.17) or death (OR, 0.98; 95% CI, 0.90-1.07). FXIII was associated with major bleeding (OR, 1.10; 95% CI, 1.02-1.2) and massive transfusion (OR, 1.25; 95% CI, 1.08-1.44). Lower baseline FXIII levels were associated with arrival from a referring hospital (FXIII level, -0.07 U/mL; 95% CI, -0.11 to -0.03), hemoglobin (FXIII level, -0.05 U/mL; 95% CI, -0.07 to -0.03), fibrinogen level (FXIII level, -0.05 U/mL; 95% CI, -0.08 to -0.02), and platelet count (FXIII level, -0.02 U/mL; 95% CI, -0.04 to -0.008). CONCLUSIONS: Baseline FXIII levels in severely injured patients were inconsistently associated with bleeding-related outcomes and mortality. However, their association with major bleeding warrants further investigation of the role of FXIII in massively transfused patients with trauma.

Gastrointestinal bleeding in von Willebrand patients: special diagnostic and management considerations.

INTRODUCTION: Severe and recurrent gastrointestinal (GI) bleeding caused by angiodysplasia is a significant problem in patients with von Willebrand disease (VWD) and in those with acquired von Willebrand syndrome (AVWS). At present, angiodysplasia-related GI bleeding is often refractory to standard treatment including replacement therapy with von Willebrand factor (VWF) concentrates and continues to remain a major challenge and cause of significant morbidity in patients despite advances in diagnostics and therapeutics. AREAS COVERED: This paper reviews the available literature on GI bleeding in VWD patients, examines the molecular mechanisms implicated in angiodysplasia-related GI bleeding, and summarizes existing strategies in the management of bleeding GI angiodysplasia in patients with VWF abnormalities. Suggestions are made for further research directions. EXPERT OPINION: Bleeding from angiodysplasia poses a significant challenge for individuals with abnormal VWF. Diagnosis remains a challenge and may require multiple radiologic and endoscopic investigations. Additionally, there is a need for enhanced understanding at a molecular level to identify effective therapies. Future studies of VWF replacement therapies using newer formulations as well as other adjunctive treatments to prevent and treat bleeding will hopefully improve care.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is caused by problems with von Willebrand factor (VWF), a protein in blood that helps stop bleeding. People with VWD either have low levels of VWF or VWF that does not work properly. The disease causes bleeding symptoms in 1 in 1000 individuals. Three main types of VWD exist. Depending on the type, people can have minimal symptoms or serious bleeding that needs hospital care.Patients with severe VWD may often experience repeated bleeding from the gastrointestinal tract. This is usually due to the formation of abnormal fragile vessels (malformations) called angiodysplasia, which have been linked to the absence or abnormal function of VWF. These fragile vessels are very difficult to find and diagnose. At present, available treatments for angiodysplasia, including long-term VWF replacement therapy, are not very effective. As a result, VWD patients with angiodysplasia have a poor quality of life.More research is needed to better evaluate current treatments and explore the contribution of abnormal VWF in the development of angiogenesis and angiodysplasia in VWD which may reveal new targets for treatment.

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.

Prevalence of Iron Deficiency and Iron-Deficiency Anemia in US Females Aged 12-21 Years, 2003-2020.

This study examines prevalence of iron deficiency among females aged 12 to 21 years to inform future screening strategies for iron deficiency and iron-deficiency anemia.

Proceedings of the immune thrombocytopenia summit: new concepts in mechanisms, diagnosis, and management.

The inaugural McMaster Immune Thrombocytopenia (ITP) Summit was held virually in 2021. The objectives of the Summit were to recognize the difficulties in establishing the diagnosis of ITP and to understand gaps in current knowledge of ITP mechanisms that might lead to better diagnostic approaches and treatments. The half-day program consisted of virtual educational sessions targeting clinicians and basic scientists. The planning committee chose 8 topics to review that would cover current knowledge and inform future research priorities. In this report, we summarized the presentations delivered at the 2021 McMaster ITP Summit and the discussions. Based on the information presented at the Summit, the following research priorities were identified: 1) investigation of platelet production as a target for ITP treatments; 2) characterization of antigen processing and antigen presentation on platelets; 3) interaction between megakaryocytes and the immune system; 4) the role for ITP gene panels; 5) the need for better methods for platelet antibody testing; 6) the role of prediction models for diagnosis and prognosis; 7) new treatment strategies, including intensification of initial therapy; and 8) personalized treatment algorithms.

Laboratory-based inequity in thrombosis and hemostasis: review of the evidence.

The concept of normal in hematology, similar to that in other areas of medicine, is anchored to the perspective of those setting the standard. This means that several laboratory reference intervals and approaches to the conditions of thrombosis and hemostasis are influenced by the vantage point of those in power. Structural inequity, including systemic racism and sexism, can lead to inappropriate normalization of disease states, such as anemia or iron deficiency, or delayed diagnoses, such as in von Willebrand disease. This review will focus on how laboratory reference intervals perpetuate the cycles of inequity in care of patients with disorders of thrombosis and hemostasis. We provide examples and case studies in maternal mortality as well as in disorders such as von Willebrand disease and iron deficiency, question physiology versus pathophysiology, acknowledge the distinction between social constructs and biologic influence, and highlight opportunities for much-needed restructuring in areas such as defining anemia and iron deficiency.