Clinical Conundrum: Return to High Altitude After Cerebral Venous Sinus Thrombosis.

Luks, Andrew M., Thomas G. DeLoughery, Jeffrey H. Gertsch, and Suzy Stokes. Clinical conundrum: return to high altitude after cerebral venous sinus thrombosis. High Alt Med Biol. 00:00-00, 2024.

AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review.

DESCRIPTION: In this Clinical Practice Update (CPU), we will Best Practice Advice (BPA) guidance on the appropriate management of iron deficiency anemia. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: No single formulation of oral iron has any advantages over any other. Ferrous sulfate is preferred as the least expensive iron formulation. BEST PRACTICE ADVICE 2: Give oral iron once a day at most. Every-other-day iron dosing may be better tolerated for some patients with similar or equal rates of iron absorption as daily dosing. BEST PRACTICE ADVICE 3: Add vitamin C to oral iron supplementation to improve absorption. BEST PRACTICE ADVICE 4: Intravenous iron should be used if the patient does not tolerate oral iron, ferritin levels do not improve with a trial of oral iron, or the patient has a condition in which oral iron is not likely to be absorbed. BEST PRACTICE ADVICE 5: Intravenous iron formulations that can replace iron deficits with 1 or 2 infusions are preferred over those that require more than 2 infusions. BEST PRACTICE ADVICE 6: All intravenous iron formulations have similar risks; true anaphylaxis is very rare. The vast majority of reactions to intravenous iron are complement activation-related pseudo-allergy (infusion reactions) and should be treated as such. BEST PRACTICE ADVICE 7: Intravenous iron therapy should be used in individuals who have undergone bariatric procedures, particularly those that are likely to disrupt normal duodenal iron absorption, and have iron-deficiency anemia with no identifiable source of chronic gastrointestinal blood loss. BEST PRACTICE ADVICE 8: In individuals with inflammatory bowel disease and iron-deficiency anemia, clinicians first should determine whether iron-deficiency anemia is owing to inadequate intake or absorption, or loss of iron, typically from gastrointestinal bleeding. Active inflammation should be treated effectively to enhance iron absorption or reduce iron depletion. BEST PRACTICE ADVICE 9: Intravenous iron therapy should be given in individuals with inflammatory bowel disease, iron-deficiency anemia, and active inflammation with compromised absorption. BEST PRACTICE ADVICE 10: In individuals with portal hypertensive gastropathy and iron-deficiency anemia, oral iron supplements initially should be used to replenish iron stores. Intravenous iron therapy should be used in patients with ongoing bleeding who do not respond to oral iron therapy. BEST PRACTICE ADVICE 11: In individuals with portal hypertensive gastropathy and iron-deficiency anemia without another identified source of chronic blood loss, treatment of portal hypertension with nonselective ß-blockers can be considered. BEST PRACTICE ADVICE 12: In individuals with iron-deficiency anemia secondary to gastric antral vascular ectasia who have an inadequate response to iron replacement, consider endoscopic therapy with endoscopic band ligation or thermal methods such as argon plasma coagulation. BEST PRACTICE ADVICE 13: In patients with iron-deficiency anemia and celiac disease, ensure adherence to a gluten-free diet to improve iron absorption. Consider oral iron supplementation based on the severity of iron deficiency and patient tolerance, followed by intravenous iron therapy if iron stores do not improve. BEST PRACTICE ADVICE 14: Deep enteroscopy performed in patients with iron-deficiency anemia suspected to have small-bowel bleeding angioectasias should be performed with a distal attachment to improve detection and facilitate treatment. Small-bowel angioectasias may be treated with ablative thermal therapies such as argon plasma coagulation or with mechanical methods such as hemostatic clips. BEST PRACTICE ADVICE 15: Endoscopic treatment of angioectasias should be accompanied with iron replacement. Medical therapy for small-bowel angioectasias should be reserved for compassionate treatment in refractory cases when iron replacement and endoscopic therapy are ineffective.

Heparin-induced Thrombocytopenia (HIT) in the DOAC Era.

OBJECTIVES: Heparin-induced thrombocytopenia (HIT) is an uncommon complication of heparin therapy with significant risk for severe morbidity and mortality. We investigated the role and outcome of direct oral anticoagulants (DOACs) for the management of HIT. METHODS: After IRB approval, a retrospective review was performed identifying all patients with positive HIT serotonin-release assays between 2020 and 2022 at two hospitals. Demographic and clinical variables were collected: initial anticoagulant, dosing and indication, interval before onset of HIT, thrombotic complications, platelet nadir and recovery, direct thrombin inhibitor (DTI) and DOAC usage, and clinical outcomes. RESULTS: 15 patients were included in the study. 8 underwent a vascular procedure, 3 had cardiac surgery, 1 patient had both and was included in both groups, and 5 patients had either non-cardiac, non-vascular surgery or no surgery. 14 patients received unfractionated heparin (93% with therapeutic dosing) and 1 received prophylactic enoxaparin prior to diagnosis of HIT. The average time to diagnosis of HIT was 10.77 days after initial anticoagulation. In-hospital mortality was 27%, related to Covid-19 infection (3/4) and intracranial hemorrhage (1/4). 40% developed thrombosis (67% venous, 33% arterial) after the diagnosis of HIT. 8/11 survivors were discharged on a DOAC. With DOAC therapy, platelet counts rebounded to an average of 265K (+/- 104.6K) within an average of 2.3 days and 364K (+/- 273.9K) within 30 days after initiation of a DOAC. No recurrent thrombosis occurred after DOAC administration and only one patient had persistent thrombocytopenia within 30 days. CONCLUSIONS: Mortality and thrombosis (arterial and venous) are common complications in patients diagnosed with HIT. In patients who survive to discharge, DOACs are the most common discharge antithrombotic agent, with low rates of recurrent thrombosis and thrombocytopenia.

Serum ferritin and risk of colonic neoplasia: Implications for the workup and treatment of iron deficiency.

Iron deficiency is the most common extraintestinal sign of colonic neoplasia, including colorectal cancer (CRC) and other lower gastrointestinal pathology. Both upper endoscopy and colonoscopy is usually recommended in the work-up of patients with unexplained iron deficiency, particularly in men and postmenopausal women. As the incidence of early-onset CRC (age <50 years) rises in the United States, there is an increasing need to identify risk predictors to aid in the early detection of CRC. It remains unknown if serum ferritin (SF), and what specific threshold, can be used as a marker to stratify those at risk for CRC and other lower gastrointestinal pathology. In this current review of the literature, we aimed to review guidelines for diagnostic workup of colonic neoplasia in the setting of iron deficiency and examine the association and specific thresholds of SF and risk of CRC by age. Some of the published findings are conflicting, and conclusions specific to younger patients are limited. Though further investigation is warranted, the cumulative findings suggest that SF, in addition to considering the clinical context and screening guidelines, may have potential utility in the assessment of colonic neoplasia.

Dermatologic manifestations of hematologic disorders.

Distinguishing key morphologic features and understanding the pathophysiology of common cutaneous manifestations of hematologic disorders is essential to ensure prompt and appropriate treatment. In fact, classic cutaneous signs may provide the first clue to the diagnosis of an underlying hematologic disease. Disorders of coagulation, vascular abnormalities, or cutaneous infiltration and deposition are responsible for the underlying pathophysiology of cutaneous manifestations in the majority of cases. Hematologists often feel ill-equipped in identifying morphologic changes in the skin. Thus, the purpose of this review is to provide a comprehensive overview of classic cutaneous manifestations and diagnostic considerations of the associated hematologic conditions. Though there is a specific focus on non-malignant disorders, those straddling the spectrum of malignancy are also discussed. In many disease states, the skin may serve as an important marker of an emerging hematologic disorder, so close collaboration and multidisciplinary input remain essential to provide optimal and timely care for these patients.

Comparison of bleeding and thrombotic outcomes in veno-venous extracorporeal membrane oxygenation: Heparin versus bivalirudin.

OBJECTIVES: We aimed to evaluate thrombotic and hemorrhagic complications with heparin versus bivalirudin use in veno-venous extracorporeal membrane oxygenation (V-V ECMO). METHODS: We performed a retrospective cohort study of adult patients placed on V-V ECMO with intravenous anticoagulation with either heparin or bivalirudin. Time to thrombotic event and major bleed were analyzed in addition to related outcomes. RESULTS: We identified 95 patients placed on V-V ECMO: 61 receiving heparin, 34 bivalirudin. The bivalirudin group had a higher rate of severe COVID-19, higher BMI, and longer ECMO duration. Despite this, bivalirudin was associated with reduced risk of thrombotic event (HR 0.14, 95% CI 0.06-0.32, p < .001) and increased average lifespan of the circuit membrane lung (16 vs. 10 days, p = 0.004). While there was no difference in major bleeding, the bivalirudin group required fewer transfusions of packed red blood cells and platelets per 100 ECMO days (means of 13 vs. 39, p = 0.004; 5 vs. 19, p = .014, respectively). Lastly, the bivalirudin group had improved survival to ECMO decannulation in univariate analysis (median OS 53 vs. 26 days, p = .015). CONCLUSIONS: In this real-world analysis of bivalirudin versus heparin, bivalirudin is a viable option for V-V ECMO and associated with lower risk of thrombotic complications and fewer transfusion requirements.

Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Undergoing Central Line Placement: A Phase 2 Clinical Trial.

BACKGROUND: Despite the ubiquitous utilization of central venous catheters in clinical practice, their use commonly provokes thromboembolism. No prophylactic strategy has shown sufficient efficacy to justify routine use. Coagulation factors FXI (factor XI) and FXII (factor XII) represent novel targets for device-associated thrombosis, which may mitigate bleeding risk. Our objective was to evaluate the safety and efficacy of an anti-FXI mAb (monoclonal antibody), gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement. METHODS: We enrolled ambulatory cancer patients undergoing central line placement to receive a single dose of gruticibart (2 mg/kg) administered through the venous catheter within 24 hours of placement and a follow-up surveillance ultrasound at day 14 for evaluation of catheter thrombosis. A parallel, noninterventional study was used as a comparator. RESULTS: In total, 22 subjects (n=11 per study) were enrolled. The overall incidence of catheter-associated thrombosis was 12.5% in the interventional study and 40.0% in the control study. The anti-FXI mAb, gruticibart, significantly prolonged the activated partial thromboplastin time in all subjects on day 14 compared with baseline (P<0.001). Gruticibart was well tolerated and without infusion reactions, drug-related adverse events, or clinically relevant bleeding. Platelet flow cytometry demonstrated no difference in platelet activation following administration of gruticibart. T (thrombin)-AT (antithrombin) and activated FXI-AT complexes increased following central line placement in the control study, which was not demonstrated in our intervention study. CRP (C-reactive protein) did not significantly increase on day 14 in those who received gruticibart, but it did significantly increase in the noninterventional study. CONCLUSIONS: FXI inhibition with gruticibart was well tolerated without any significant adverse or bleeding-related events and resulted in a lower incidence of catheter-associated thrombosis on surveillance ultrasound compared with the published literature and our internal control study. These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465760.

Sex, lies, and iron deficiency: a call to change ferritin reference ranges.

Iron deficiency is a very common and treatable disorder. Of all the tests available to diagnose iron deficiency, the serum ferritin is the most able to discriminate iron deficiency from other disorders. However, the reference range for ferritin in many laboratories will lead to underdiagnosis of iron deficiency in women. Studies have shown that 30%-50% of healthy women will have no marrow iron stores, so basing ferritin cutoffs on the lowest 2.5% of sampled ferritins is not appropriate. In addition, several lines of evidence suggest the body physiologic ferritin "cutoff" is 50  ng/mL. Work is needed to establish more realistic ferritin ranges to avoid underdiagnosing a readily treatable disorder.

Psychological toxicity in classical hematology.

Although considered "benign," mild blood count abnormalities, genetic factors imparting inconsequential thrombotic risk, and low-risk premalignant blood disorders can have significant psychological and financial impact on our patients. Several studies have demonstrated that patients with noncancerous conditions have increased levels of anxiety with distress similar to those with malignancy. Additionally, referral to a classical hematologist can be a daunting process for many patients due to uncertainties surrounding the reason for referral or misconstrued beliefs in a cancer diagnosis ascribed to the pairing of oncology and hematology in medical practice. If not properly triaged, incidental laboratory abnormalities can trigger extensive and costly evaluation. These challenges are compounded by a lack of consensus guidance and generalizability of modern reference ranges that do not adequately account for common influencing factors. Although often benign, incidental hematologic findings can lead to emotional suffering and careful consideration of the potential psychological and financial duress imparted to an individual must be considered. In this article, we will review the current literature describing the psychological effect of some commonly known hematologic conditions, identify benign causes for variations in hematologic laboratory values, and provide recommendations to reduce psychological toxicity as it pertains to hematologic testing.

Estrogen-based hormonal therapy and the risk of thrombosis in COVID-19 patients.

OBJECTIVE: Estrogen-containing contraceptives and hormone replacement therapy are used commonly, however, the risks of venous and arterial thrombosis imparted by such medications during COVID-19 infection or other similar viral infections remain undescribed. METHODS: To assess the risk of venous and arterial thrombosis in patients receiving oral estrogen-containing therapy (ECT) with COVID-19 as compared to those receiving non-estrogen-based hormonal therapy, we conducted a multicenter cohort study of 991 patients with confirmed COVID-19 infection, 466 receiving estrogen-containing hormonal therapy, and 525 receiving progestin-only or topical therapy. RESULTS: The use of estrogen-containing therapy was found to significantly increase the risk of venous thromboembolism (VTE) following COVID-19 diagnosis after controlling for age (HR 5.46 [95% CI 1.12-26.7, p = .036]). This risk was highest in patients over age 50, with 8.6% of patients receiving estrogen-containing therapy diagnosed with VTE compared to 0.9% of those receiving non-estrogen-based therapies (p = .026). The risk of arterial thrombosis was not significantly associated with oral estrogen use. CONCLUSIONS: These results suggest that estrogen-containing therapy is associated with a significantly increased risk of VTE in COVID-19 patients, especially in older individuals. These findings may guide provider counseling and management of patients with COVID-19 on estrogen-containing therapy.

In noncritical COVID-19, therapeutic vs. prophylactic anticoagulation did not reduce a composite adverse clinical outcome at 30 d.

SOURCE CITATION: Stone GW, Farkouh ME, Lala A, et al; FREEDOM COVID Anticoagulation Strategy Randomized Trial Investigators. Randomized trial of anticoagulation strategies for noncritically ill patients hospitalized with COVID-19. J Am Coll Cardiol. 2023;81:1747-1762. 36889611.

A Survey of Ski Patrols in the United States Comparing Medical Direction, Patroller Training, and Patient Care.

INTRODUCTION: Ski patrols are tasked with substantial challenges: distance from definitive care, complex extrications, and winter environments. Rules for US ski patrols stipulate that ≥1 persons be trained in basic first aid, but no further regulations regarding the specifics of provided medical care exist. This project investigated patroller training, patient care, and medical direction of US ski patrols through a survey of ski patrol directors and medical directors. METHODS: Participants were contacted via email, phone, and personal contacts. After consultation with known ski patrol directors and medical directors for question guidance, 2 separate institutional review board-approved surveys were designed: 1 for ski patrol directors and 1 for ski patrol medical directors, containing 28 and 15 qualitative questions, respectively. The surveys were distributed with a link to the encrypted Qualtrics survey platform. After 2 reminders and 4 mo, results were downloaded from Qualtrics into an Excel spreadsheet. RESULTS: Twenty-two responses from patrol directors and 15 from medical directors were received. The response rate is unknown. Outdoor emergency care certification was the minimum medical training required by 77% of the study participants. Twenty-seven percent of surveyed patrols belonged to an emergency medical service agency. Fifty percent of 11 surveyed ski patrols had a medical director, 6 of whom were board certified in emergency medicine. All surveyed medical directors stated that they assisted with patroller education, and 93% assisted with protocol development. CONCLUSIONS: The surveys demonstrated variability in patroller training, protocols, and medical directorship. The authors questioned whether ski patrols would benefit from increased standardization of care and training, quality improvement programs, and medical directorship.

In symptomatic isolated DVT, 12 wk vs. 6 wk of rivaroxaban reduced recurrent VTE at 24 mo.

SOURCE CITATION: Ageno W, Bertu L, Bucherini E, et al; RIDTS study group. Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial. BMJ. 2022;379:e072623. 36520715.

Clinical outcomes of patients referred for asymptomatic neutropenia: A focus on racial disparities in hematology.

BACKGROUND: Asymptomatic neutropenia is a common hematology referral, though standardized reference ranges and published clinical outcomes are lacking. METHODS: In our retrospective analysis, we evaluated demographics, laboratory, and clinical outcomes of adult patients referred to an academic hematology practice for evaluation of neutropenia from 2010 to 2018. Primary and secondary outcomes included incidence of hematologic disorders and rates of Duffy-null positivity by race, respectively. In a separate analysis, we reviewed absolute neutrophil count (ANC) reference ranges from publicly available Association of American Medical Colleges Medical School Member laboratory directories to assess institutional variations. RESULTS: In total, 163 patients were included, with disproportionate number of Black patients referred compared to local demographics. Twenty-three percent of patients (n = 38) were found to have a clinically relevant hematologic outcome (mean ANC of 0.59 × 109 /L), and only six were identified with ANC ≥1.0 × 109 /L. Incidence of hematologic outcomes was lowest among Black patients (p = .05), and nearly all Blacks who underwent Duffy-null phenotype testing were positive (93%), compared to 50% of Whites (p = .04). In separate review of laboratory directories, we confirmed wide variation in ANC lower limit of normal (0.91-2.40 × 109 /L). CONCLUSION: Hematologic disorders were rare in patients with mild neutropenia and among Blacks, highlighting the need to standardize hematological ranges representative of non-White communities.

Desmopressin as a hemostatic and blood sparing agent in bleeding disorders.

Intranasal, subcutaneous, or intravenous desmopressin can be utilized to release von Willebrand Factor and Factor VIII into circulation, enhance platelet adhesion and shorten bleeding time. Due to these properties, desmopressin can be effective in controlling bleeding in mild hemophilia A, certain subtypes of von Willebrand disease and in acute bleeding from uremia, end stage renal disease, and liver disease. Its use, however, can be complicated by hyponatremia and rarely arterial thrombotic events. While desmopressin has also been used as a prophylactic blood sparing agent in orthopedic, renal, and hepatic procedures, clinical studies have shown limited benefit in these settings. The purpose of this article is to review the evidence for desmopressin in primary hematologic disorders, discuss its mechanism of action and evaluate its utility as a hemostatic and blood sparing product in various bleeding conditions.

The role of oral iron in the treatment of adults with iron deficiency.

Iron deficiency is the most common nutrient deficiency in the world, affecting over 20% of premenopausal women worldwide. Oral iron supplementation is often the first-line treatment for the acute and chronic management of iron deficiency due to its ease and accessibility. However, there is no consensus on the optimal formulation or dosing strategy, or which patients should be preferentially treated with intravenous iron. Management of iron deficiency is complicated by the hepcidin-ferroportin iron regulatory pathway, which has evolved to prevent iron overload and thereby creates an inherent limit on gastrointestinal iron uptake and efficacy of oral iron. Unabsorbed iron propagates many of the side effects that complicate oral iron use including dyspepsia and constipation, all of which can thus be exacerbated by excessive oral iron doses. Daily low dose and every other day dosing protocols have attempted to bypass this physiologic bottleneck to allow for effective absorption and limit side effects; however, this approach has still resulted in low fractional iron absorption. In the following manuscript, we review the pathophysiology of iron absorption and current evidence for various preparations of oral iron. Lastly, we highlight opportunities for further study to advance the care of individuals affected by iron deficiency.

Hematologic concerns in transgender patients.

Patients with gender dysphoria are increasingly seeking gender-affirming therapies, which can have adverse hematologic effects. For example, estrogen can increase the risk for arterial and venous thrombosis, whereas testosterone can cause erythrocytosis. This article reviews the hematologic issues associated with gender-affirming hormone therapies and discusses ways to lessen and monitor the risks. Common consult scenarios are also addressed.