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INTRODUCTION—: Long-distance travel is assumed to be a risk factor for venous thromboembolism (VTE). However, the available data have not clearly demonstrated the strength of this relationship, nor have they shown evidence for the role of thromboprophylaxis. METHODS—: We performed a systematic review of the literature. We also summarized available guidelines from 5 groups. RESULTS—: We found 18 studies that addressed this question. Based on the data presented in the review, we conclude that there is an association between VTE and length of travel, but this association is mild to moderate in effect size with odds ratios between 1.1 and 4. A dose-response relationship between VTE and travel time was identified, with a 26% higher risk for every 2 h of air travel (P=0.005) starting after 4 h. The quality of evidence for both travel length and thromboprophylaxis was low. However, low-risk prophylactic measures such as graduated compression stockings were shown to be effective in VTE prevention. There is heterogeneity among the different practice guidelines. The guidelines generally concur that no prophylaxis is necessary in travelers without known thrombosis risk factors and advocate for conservative treatment such as compression stockings over pharmacologic prophylaxis. CONCLUSIONS—: We conclude air travel is a risk factor for VTE and that there is a dose relationship starting at 4 h. For patients with risk factors, graduated compression stockings are effective prophylaxis.

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.

DeLoughery, Thomas G. Anemia at altitude-thalassemia, sickle cell disease, and other inherited anemias. High Alt Med Biol. 22: 113-118, 2021.-Anemia due to any etiology is a common medical condition throughout the world. This article discusses the most common inherited anemia types-sickle cell disease and trait, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase deficiency. The implications of anemia for travel at altitude are discussed, and suggestions for counsel and preparations for such travel are presented.

Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single‐infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.

DeLoughery, Emma P. and Thomas G. DeLoughery. Review and Analysis of Mountaineering Accidents in the United States from 1947-2018.

Extracorporeal membrane oxygenation (ECMO) causes both thrombosis and bleeding. Major society guidelines recommend continuous, systemic anticoagulation to prevent thrombosis of the ECMO circuit, though this may be undesirable in those with active, or high risk of, bleeding. We aimed to systematically review thrombosis and bleeding outcomes in published cases of adults treated with ECMO without continuous systemic anticoagulation. Ovid MEDLINE, Cochrane CENTRAL and CDSR, and hand search via SCOPUS were queried. Eligible studies were independently reviewed by two blinded authors if they reported adults (≥18 years) treated with either VV- or VA-ECMO without continuous systemic anticoagulation for ≥24 hours. Patient demographics, clinical data, and specifics of ECMO technology and treatment parameters were collected. Primary outcomes of interest included incidence of bleeding, thrombosis of the ECMO circuit requiring equipment exchange, patient venous or arterial thrombosis, ability to wean off of ECMO, and mortality. Of the 443 total publications identified, 34 describing 201 patients met our inclusion criteria. Most patients were treated for either acute respiratory distress syndrome or cardiogenic shock. The median duration of anticoagulant-free ECMO was 4.75 days. ECMO circuity thrombosis and patient thrombosis occurred in 27 (13.4%) and 19 (9.5%) patients, respectively. Any bleeding and major or "severe" bleeding was reported in 66 (32.8%) and 56 (27.9%) patients, respectively. Forty patients (19%) died. While limited by primarily retrospective data and inconsistent reporting of outcomes, our systematic review of anticoagulant-free ECMO reveals an incidence of circuity and patient thrombosis comparable to patients receiving continuous systemic anticoagulation while on ECMO.

Background Reluctance to use intravenous (IV) iron for the treatment of iron deficiency continues due to a perceived high risk of severe hypersensitivity reactions (HSRs). Additionally, it has been hypothesized that 'dextran-derived' IV iron products (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than 'non-dextran-derived' products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). In the present analysis, HSR data from head-to-head randomized controlled trials (RCTs) with IV iron products were evaluated to determine if differences in safety signals are present among these IV iron formulations. Study design and methods Reported serious or moderate-to-severe HSR incidence data from five RCTs (FIRM; FERWON-NEPHRO/-IDA; PHOSPHARE-IDA04/-IDA05) were used to calculate risk differences with 95% confidence intervals (CIs) for FER, FCM, FDI, and IS. The rates and risk differences for these HSRs were compared. Results The analysis included data for 5247 patients: FER (n = 997), FCM (n = 1117), FDI (n = 2133) and IS (n = 1000). Overall rates of serious or moderate to severe HSRs were low (0.2%-1.7%). The risk differences (95% CIs) showed small differences between the IV iron formulations: FER versus FCM, -0.1 (-0.8 to 0.6); FDI versus IS, 0.1 (-0.3 to 0.5); FDI versus FCM, -0.9 (-3.7 to 1.9). Conclusion RCT evidence confirms a low risk of serious or moderate to severe HSRs with newer IV iron formulations and no significant differences among existing commercially available products. Thus, RCT data show that the supposed classification of dextran-derived versus non-dextran-derived IV iron products has no clinical relevance.

Thrombotic Microangiopathy (TMA) is a heterogeneous collection of syndromes that encompasses TTP, HUS, and other processes characterized by thrombocytopenia, microangiopathic hemolytic anemia, and, if untreated, organ failure and death. Novel therapies have recently been approved for the management of certain thrombotic microangiopathies, including caplacizumab for immune-mediated TTP, and eculizumab for atypical HUS. These options have complicated the standard workflow, which includes initiation of plasma exchange until ADAMTS13 testing can be resulted. Given such results may take several days, there is indecision regarding the appropriate initial management of TMA. Decisions regarding caplacizumab and eculizumab are complex, and include considerations over costs, side effects, and efficacy. In the following forum, we discuss the current data and pose possible management strategies in patients with TMA before final diagnosis can be obtained.

Iron deficiency anemia (IDA) is the most prevalent and treatable form of anemia worldwide. The clinical management of patients with IDA requires a comprehensive understanding of the many etiologies that can lead to iron deficiency including pregnancy, blood loss, renal disease, heavy menstrual bleeding, inflammatory bowel disease, bariatric surgery, or extremely rare genetic disorders. The treatment landscape for many causes of IDA is currently shifting toward more abundant use of intravenous (IV) iron due to its effectiveness and improved formulations that decrease the likelihood of adverse effects. IV iron has found applications beyond treatment of IDA, and there is accruing data about its efficacy in patients with heart failure, restless leg syndrome, fatigue, and prevention of acute mountain sickness. This review provides a framework to diagnose, manage, and treat patients presenting with IDA and discusses other conditions that benefit from iron supplementation.

Machine learning has the potential to improve identification of patients for appropriate diagnostic testing and treatment, including those who have rare diseases for which effective treatments are available, such as acute hepatic porphyria (AHP). We trained a machine learning model on 205 571 complete electronic health records from a single medical center based on 30 known cases to identify 22 patients with classic symptoms of AHP that had neither been diagnosed nor tested for AHP. We offered urine porphobilinogen testing to these patients via their clinicians. Of the 7 who agreed to testing, none were positive for AHP. We explore the reasons for this and provide lessons learned for further work evaluating machine learning to detect AHP and other rare diseases.

Iron deficiency anemia (IDA) and heavy menstrual bleeding are prevalent, interrelated issues impacting over 300 million premenopausal women worldwide. IDA is generally associated with increased platelet counts; however, the effects of IDA and its correction on platelet function in premenopausal women remain unknown.We sought to determine how IDA and intravenous iron affect platelet count and platelet function in premenopausal women.Hematologic indices were assessed in a multicenter, retrospective cohort of 231 women repleted with intravenous iron. Pre- and postinfusion blood samples were then obtained from a prospective cohort of 13 women to analyze the effect of intravenous iron on hematologic parameters as well as platelet function with flow cytometry and platelet aggregation assays under physiologic shear.Following iron replacement, anemia improved, and mean platelet counts decreased by 26.5 and 16.0 K/mmWe find that intravenous iron improves anemia while restoring platelet counts and platelet secretory responses in premenopausal women with iron deficiency. Our results suggest that iron deficiency as well as iron replacement can have a range of effects on platelet production and function. Consequently, platelet reactivity profiles should be further examined in women and other groups with IDA where replacement offers a promising means to improve anemia as well as quality of life.

Objective Evans syndrome, the combination of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) or autoimmune neutropenia, is associated with a high rate of relapsed/refractory disease. There are limited data on the efficacy of splenectomy for this condition. We reviewed patient outcomes after splenectomy for Evans syndrome compared to ITP at our institution. Methods We performed a retrospective analysis of patients who underwent splenectomy for autoimmune cytopenias over a 23-year period with the intention of comparing disease relapse rates after splenectomy in patients with Evans syndrome and in those with ITP. Results During the study period, 77 patients underwent splenectomy for ITP and seven underwent splenectomy for Evans syndrome. In the Evans cohort, splenectomy led to an 85.7% initial response rate with a 42.8% rate of relapse within one year and a long-term (one-year) response rate of 42.8%. In the ITP cohort, the initial response rate was 90.9% with a long-term response rate of 70.1%. Conclusion Our data suggest that long-term remission rates after splenectomy are lower in adults with Evans syndrome compared to those with ITP, although splenectomy may still be an acceptable treatment for certain patients with Evans syndrome. Our findings underscore the need for further research and development of additional therapeutic strategies for this patient population.

Hemostatic complications are common in patients with ventricular assist devices. The pathophysiologic mechanisms that lead to dysregulated hemostasis involve complex interactions between device surface, sheer stress, and blood flow. These factors lead to various manifestations that require a thorough understanding of the interplay among platelets, coagulation factors, and red cells. In this article, we review the pathophysiology of hematologic complications (bleeding, acquired von Willebrand disease, heparin‐induced thrombocytopenia, hemolysis, stroke and pump thrombosis), the clinical manifestations, and the management of each. We summarize the evidence available for management of these entities and provide a pragmatic clinical review.

As the adverse effects of iron deficiency are better recognized, the use of oral and intravenous iron has increased dramatically. Oral iron is often poorly tolerated, with up to 70% or more of patients noting gastrointestinal issues; this may affect adherence to therapy. In addition, many patients will not respond to oral iron due to their underlying illness. Intravenous iron is being used more frequently to replete iron stores. True anaphylaxis is very rare, but complement-mediated infusion reactions may be seen in up to 1 in every 200 patients. Previous concerns about intravenous iron increasing the risk of infection or cardiovascular disease are unfounded.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

The use of blood transfusions is a mainstay of modern medical practice. Jehovah's Witnesses decline the use of blood transfusions as a matter of faith, however, and other patients do so for personal reasons. In all cases, it is important to document what blood products can or cannot be used. It is also essential to test all patients for iron deficiency, and to address any correctable factors in those who are anemic. This article reviews a variety of options that are available to aid in caring for patients who refuse blood transfusions, ranging from tranexamic acid to erythropoiesis-stimulating agents. With the use of these treatments, patients who decline blood transfusion can be safely managed in situations ranging from elective surgery to stem cell transplant to pregnancy.

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.

IMPORTANCE: Mechanical heart valves (MHVs) pose significant thrombogenic risks to pregnant women and their fetuses, yet the choice of anticoagulation in this clinical setting remains unclear. Various therapeutic strategies carry distinct risk profiles that must be considered when making the decision about optimal anticoagulation. OBJECTIVE: We sought to review existing data and offer recommendations for the anticoagulation of pregnant women with MHVs, as well as management of anticoagulation in the peripartum period. EVIDENCE ACQUISITION: We performed a literature review of studies examining outcomes in pregnant women receiving systemic anticoagulation for mechanical valves, and also reviewed data on the safety profiles of various anticoagulant strategies in the setting of pregnancy. RESULTS: Warfarin has been shown to increase rates of embryopathy and fetal demise, although it has traditionally been the favored anticoagulant in this setting. Low-molecular-weight heparin, when dosed appropriately with close therapeutic monitoring, has been shown to be safe for both mother and fetus. CONCLUSIONS AND RELEVANCE: We favor the use of low-molecular-weight heparin with appropriate dosing and monitoring for the anticoagulation of pregnant women with MHVs. Data suggest that this approach minimizes the thrombotic risk associated with the valve while also providing safe and effective anticoagulation that can be easily managed in the peripartum period. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians. LEARNING OBJECTIVES: After completing this activity, the learner should be better able to: describe the clinical considerations in choosing an anticoagulation strategy for a pregnant patient with an MHV; evaluate the existing data about the safety profile of various anticoagulation strategies and the potential benefits and risks of each approach to the mother and fetus; and discuss one recommended approach to management of mechanical valves in the pregnant patient and assess the clinical nuances associated with each individual patient’s decision.

BackgroundWith the growing adoption of the electronic health record (EHR) worldwide over the last decade, new opportunities exist for leveraging EHR data for detection of rare diseases. Rare diseases are often not diagnosed or delayed in diagnosis by clinicians who encounter them infrequently. One such rare disease that may be amenable to EHR-based detection is acute hepatic porphyria (AHP). AHP consists of a family of rare, metabolic diseases characterized by potentially life-threatening acute attacks and, for some patients, chronic debilitating symptoms that negatively impact daily functioning and quality of life. The goal of this study was to apply machine learning and knowledge engineering to a large extract of EHR data to determine whether they could be effective in identifying patients not previously tested for AHP who should receive a proper diagnostic workup for AHP.Methods and FindingsWe used an extract of the complete EHR data of 200,000 patients from an academic medical center for up to 10 years longitudinally and enriched it with records from an additional 5,571 patients from the center containing any mention of porphyria in notes, laboratory tests, diagnosis codes, and other parts of the record. After manually reviewing all patients with the ICD-10-CM code E80.21 (Acute intermittent [hepatic] porphyria), we identified 30 patients who were positive cases for our machine learning models, with the rest of the patients used as negative cases. We parsed the record into features, which were scored by frequency of appearance and labeled by the EHR source document. We then carried out a univariate feature analysis, manually choosing features not directly tied to provider attributes or suspicion of the patient having AHP. We next trained on the full dataset, with the best cross-validation performance coming from support vector machine (SVM) algorithm using a radial basis function (RBF) kernel. The trained model was applied back to the full data set and patients were ranked by margin distance. The top 100 ranked negative cases were manually reviewed for symptom complexes similar to AHP, finding four patients where AHP diagnostic testing was likely indicated and 18 patients where AHP diagnostic testing was possibly indicated. From the top 100 ranked cases of patients with mention of porphyria in their record, we identified four patients for whom AHP diagnostic testing was possibly indicated and had not been previously performed. Based solely on the reported prevalence of AHP, we would have expected only 0.002 cases out of the 200 patients manually reviewed.ConclusionsThe application of machine learning and knowledge engineering to EHR data may facilitate the diagnosis of rare diseases such as AHP. The only manual modifications to this work were the removal of disease-specific or medical center specific features that might undermine our ability to find new cases. Further work will recommend clinical investigation to identified patients’ clinicians, evaluate more patients, assess additional feature selection and machine learning algorithms, and apply this methodology to other rare diseases.

Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.

The terminal complement-inhibitor eculizumab has dramatically changed the management of patients with atypical hemolytic uremic syndrome (aHUS), and has also shown promise for treating certain forms of secondary HUS (sHUS), including that caused by drugs and solid-organ/hematopoietic stem cell transplant. While effective, eculizumab is costly and inconvenient. In this review, we evaluate the literature on eculizumab cessation in these diseases to better inform clinicians who consider stopping therapy. Reported relapse rates in aHUS after stopping eculizumab are as high as 30%, suggesting indefinite therapy is reasonable and that patients who choose to stop should be closely monitored. In sHUS, relapse is rare, justifying short courses of eculizumab.

Background: Iron deficiency, heavy menstrual bleeding, and anemia are interrelated conditions with high prevalence in women's health. Together, they impact an estimated 310 million premenopausal women worldwide. Iron deficiency has been associated with development of anemia as well as thrombocytosis. However, the effects of iron deficiency on platelet function remain unknown. Objective: We set out to investigate the impact of IV iron repletion on platelet function, platelet count, and other blood cell indices in iron deficient premenopausal women. Methods: We conducted a prospective single-center study of iron deficient premenopausal women who underwent iron repletion with a single dose of 1000 mg of low molecular weight iron. Pre-infusion and post-infusion blood samples were obtained for laboratory analysis. Standard of care monitoring of iron indices and complete blood counts were also included in the analysis. Pre-infusion rates of anemia and thrombocytosis were calculated using minimum hemoglobin and peak platelet count in the 6 months preceding iron infusion. Platelet function was quantified by Fluorescence-Activated Cell Sorting (FACS) quantification of platelet activation marker antibodies for GPIIb/IIIa (PAC1) and P-selectin (CD62P) after exposure to multiple platelet agonists. Platelet aggregation was assessed by flow of anticoagulated whole blood at a shear rate of 300 s -1 for 5 minutes through chambers coated with type I collagen, imaged with differential interference contrast optics, and quantitatively represented through computation of percent total surface coverage. Pre-infusion and post-infusion cell indices and aggregation data were compared by paired samples t-test. All statistical analyses were performed in GraphPad Prism (Version 8.0.0). Results: Thirteen patients were included in the analysis. Heavy menstrual bleeding was the suspected cause of iron deficiency in 83% of patients. Thrombocytosis was present in 15% of patients at pre-infusion and no patients at post-infusion. Average ferritin was 14 µg/L at pre-infusion and 126 µg/L at post-infusion. The peak platelet count within 6 months pre-infusion was 309 K/mm 3 (±89) vs. 274 (±64) K/mm 3 at post-infusion (p Conclusion: Correction of iron deficiency results in decreased platelet count and improves platelet aggregation over collagen. Iron repletion may also improve platelet reactivity in response to physiologic agonists. These findings may suggest that iron deficiency impairs hemostasis and that correction of low iron may be even more critical for women with heavy menstrual bleeding. Figure 1 Figure 1. Disclosures Shatzel: Aronora Inc,: Consultancy.

Enzalutamide, a novel, oral androgen receptor antagonist used for the treatment of metastatic, castration-resistant prostate cancer, has been shown to improve overall and progression-free survival, prolong time to initiation of chemotherapy, reduce skeletal-related events, and carry a favorable adverse effect profile. Metastatic prostate cancer is a disease of older men, a population with an increased incidence of medical comorbidities warranting anticoagulation. Prostate cancer itself, along with some of its therapies, is also prothrombotic. Enzalutamide interacts with several anticoagulants through various mechanisms, making their concurrent use clinically challenging. As such, complex decisions about anticoagulation in these patients are frequently encountered by treating physicians. In this review, we describe the potential interactions between enzalutamide and various anticoagulants, and suggest management paradigms based on the current body of knowledge for patients with atrial fibrillation, venous thromboembolism, and mechanical heart valves.

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell-mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared with standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. In addition, the potential cardiovascular protective effects of ibrutinib monotherapy in patients at risk of vascular disease are unknown. Patients should be cautioned against using non-steroidal anti-inflammatory drugs, fish oils, vitamin E and aspirin-containing products, and consider replacing ibrutinib with a different agent if dual antiplatelet therapy is indicated. Patients should not take vitamin K antagonists concurrently with ibrutinib; direct oral anticoagulants should be used if extended anticoagulation is strongly indicated. In this review, we describe the pathophysiology of ibrutinib-mediated bleeding and suggest risk reduction strategies for common clinical scenarios associated with ibrutinib.

Clinicians, including hematologists, are more frequently encountering transgender individuals in practice; however, most lack training on the management and complications of transgender medicine. Hormonal therapy forms the backbone of medical interventions for patients undergoing gender transition. While supplementing an individual's intrinsic sex hormone is associated with a variety of hematologic complications including increased rates of venous thrombosis, cardiovascular events, erthyrocytosis, and malignancy, the risks of supplementing with opposing sex hormones are not well understood. Data on the hematologic complications of these therapies are accumulating but remain limited, and clinicians have little experience with their management. This review highlights the current interventions available in transgender medicine and related potential hematologic complications, and it suggests simple, evidence-based management going forward. Am. J. Hematol. 92:204-208, 2017. © 2016 Wiley Periodicals, Inc.

Background and Aims: This study aimed to understand the use of massive transfusion (MT) for gastrointestinal bleeding (GIB). Patients and Methods: We performed a retrospective analysis of patients admitted to our medical Intensive Care Unit (ICU) with GIB for the type of bleeding, quantity of blood products transfused, and risk of transfusion-related acute lung injury (TRALI) and death. MT was defined as transfusion of 10 or more units of red blood cell (RBC) within a 24-h period in a 1-unit RBC: 1-unit fresh frozen plasma: and 1-unit platelet ratio. TRALI was defined as development of acute lung injury (ALI), within 6 h of transfusion, with new bilateral pulmonary infiltrates, absence of circulatory overload, or other explanation for ALI. Results: In a 43-month interval, 169 patients were admitted to the ICU with GIB and received blood products, of whom 13 received MT. Ten patients developed TRALI, of whom 7 (70%) had received MT. MT was associated with an increased risk of TRALI (odds ratio [OR]: 17.9, 95% confidence interval [CI]: 2.9–111.2, P = 0.002) after adjusting for age, sex, body mass index, baseline vitals, and laboratory data. Death was predicted by MT (OR: 5.6, 95% CI: 1.6–19.7, P = 0.007), TRALI (OR: 2.3, 95% CI: 1.1–4.6, P = 0.02), and Acute Physiologic Chronic Health Evaluation II score (OR: 1.17 per unit increase, 95% CI: 1.09–1.26, P < 0.001) after adjusting for age and sex. Conclusions: MT for GIB is associated with an increased risk of TRALI and death. Prospective studies assessing the use of MT in this population are needed to understand and improve outcomes.

Chronic liver disease (CLD) alters normal hemostatic and thrombotic systems via multiple mechanisms including reduced platelet function and number, leading to challenging peri-operative planning. Hepatic thrombopoietin (TPO) synthesis is reduced in CLD, leading to several recent randomized, placebo-controlled trials examining the utility of TPO-mimetics to increase platelet counts prior to surgery. While these trials do suggest that TPO-mimetics are efficacious at increasing platelet counts in patients with CLD and have led to several recent drug approvals in this space by the U.S. Food & Drug Administration, it remains unclear whether these results translate to the relevant clinical endpoint of reduced perioperative bleeding rate and severity. In this article, we review several recently-published, phase 3 trials on the TPO-mimetics eltrombopag, avatrombopag and lusutrombopag, and discuss the clinical significance of their results.

Hereditary haemochromatosis, one of the most common genetic disorders in the United States, can produce systemic iron deposition leading to end-organ failure and death if untreated. The diagnosis of this condition can be challenging as elevated serum ferritin may be seen in a variety of conditions, including acute and chronic liver disease, a range of systemic inflammatory states, and both primary and secondary iron overload syndromes. Appropriate and timely diagnosis of haemochromatosis is paramount as simple interventions, such as phlebotomy, can prevent or reverse organ damage from iron overload. The recognition of other aetiologies of elevated ferritin is also vital to ensure that appropriate intervention is provided and phlebotomy only utilized in patients who require it. In this review, we summarize the existing data on the work up and management of hereditary haemochromatosis and present a practical algorithm for the diagnosis and management of this disease.

Despite therapeutic anticoagulation, patients with venous thromboembolism (VTE) not uncommonly present with findings of progressive thrombosis, sometimes within the first several weeks of treatment. While the prevailing strategy in these scenarios is to assume the current anticoagulant is ineffective and to switch to a different drug class, this practice may be unnecessary. Numerous trials of heparins and vitamin K antagonists for VTE have demonstrated that asymptomatic thrombus propagation despite therapeutic anticoagulation is common. While similar, serial imaging studies after initial VTE have not been replicated in trials of the direct oral anticoagulants, we reason that asymptomatic thrombus propagation detected within the first month of VTE diagnosis can be managed with continuation of the current anticoagulant strategy and close follow‐up for worsening or recurrent symptoms.

To the editor: The risk for venous thromboembolism (VTE) is increased significantly in hospitalized patients, which can lead to morbidity and, rarely, mortality.[1][1],[2][2] Thromboprophylaxis with low-dose anticoagulation for up to 14 days during hospitalization has been shown to decrease the

Background The direct antiglobulin test (DAT) is frequently ordered by both hematologists and non-hematology medical professionals in the workup of possible allo- or autoimmune hemolytic anemias. Frustratingly, positive DAT results in the absence of other abnormal blood hemolysis biomarkers can be challenging to interpret, as published data on the frequency of these "false-positive" DATs is limited. We sought to characterize the frequency of "false-positive" DATs and describe potential associations with co-morbid diseases, in order to better define the diagnostic accuracy of the DAT for allo- or autoimmune hemolysis. Methods After obtaining appropriate Institutional Review Board approval, we identified all positive DAT results from Oregon Health & Science University during the calendar year between January and December 2019. Electronic medical records of the patients associated with these positive DAT results were individually reviewed, with collected data including patient demographics, specific pattern of DAT positivity (IgG, C3 or both), reason for obtaining DAT (suspicion for autoimmune hemolysis or transfusion, or as part of preparatory workup for possible blood product transfusion), hemolysis biomarkers (CBC, reticulocytes, LDH, haptoglobin, total and direct bilirubin), recent blood product transfusion or IVIG administration within the preceding 6 months, and co-morbid illnesses. True positive DAT results were considered those concurrent with at least one other positive blood hemolysis biomarker, or those in patients with a pre-existing diagnosis of autoimmune hemolytic anemia or Evans syndrome. Results 182 positive DAT tests among 134 individual patients were identified within the specified time period. 65 of these were obtained in the ambulatory setting, and 117 as inpatient. The majority of DAT results were positive for IgG only (165 of 182, 90.7%), with 17 of 182 (9.3%) positive for both IgG and C3, and no instances of isolated C3 positivity. The median values for hemolysis biomarkers were as follows: LDH 307, total bilirubin 0.9, and haptoglobin 80. Of the 134 patients with positive DAT results, 48 (36%) had at least one other positive or elevated blood biomarker of hemolysis, and 31 (23%) had two or more positive biomarkers. 55 records (41%) had no other associated findings of hemolysis, and 31 patients had not had hemolysis biomarkers drawn. 53 of 134 patients (40%) had DATs checked as part of alloantibody workup prior to potential blood product transfusion. The calculated rate of DAT positivity concurrent with other positive hemolysis biomarkers was 79 of 134 (59%), and DATs without other signs of hemolysis were seen in 55 of 134 (41%). Among patients with DAT results without signs of hemolysis, common co-morbid illnesses/conditions included recent blood product transfusion, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, hypothyroidism, and cirrhosis. The majority of patients had received blood product transfusion or IVIG within the preceding 6 months (94 out of 134 [70%]). Discussion In this single-center retrospective analysis, we found a substantial rate of DAT positivity for IgG, or combined IgG and C3, without other laboratory biomarkers of hemolysis. While many of these non-hemolysis-related positive DAT results could be considered false positives, a substantial proportion of patients had also received blood product transfusion or IVIG within the previous 6 months, and thus a large fraction of included patients may have had positive DATs related to previous alloimmunization and lingering "bystander" hemolysis or agglutination of autologous red blood cells. In addition, co-morbid hepatic, autoimmune or hematologic diseases were common among this cohort, corroborating findings in previously published analyses. In summary, we found a clinically meaningful rate of false-positive DAT results in both ambulatory and inpatient settings. We posit that a positive DAT result, in isolation, need not drive extensive hemolysis workup, given the frequent association with prior blood product transfusions and numerous co-morbid illnesses. Disclosures No relevant conflicts of interest to declare.

While cardiovascular disease is common, occasionally hematologists and other practitioners will encounter patients with arterial thrombosis/infarction in unusual sites, without clear cause or obvious diagnostic and treatment paradigms. Contrary to the more commonly encountered cerebrovascular accident and cardiovascular disorders, the various infarctions outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review outlines the current literature on arterial thrombosis, with consideration given to anatomic sources and hypercoagulable associations, while focusing on the epidemiology, pathophysiology, provoking factors, and current recommended treatments for intracardiac thrombus, primary aortic mural thrombus, visceral infarctions, and cryptogenic limb ischemia to provide a useful and practical review for the practitioner.

DeLoughery, Thomas G. Anticoagulation considerations for travel to high altitude. High Alt Med Biol 16:181-185, 2015.-An increasing percentage of the population are on anticoagulation medicine for clinical reasons ranging from stroke prevention in atrial fibrillation to long term prevention of deep venous thrombosis. In recent years, several new direct oral anticoagulants have entered the market. The key questions that should be kept in mind when approaching a potential traveler on anticoagulation are: 1) why is the patient on anticoagulation? 2) do they need to stay on anticoagulation? 3) what are the choices for their anticoagulation? 4) will there be any drug interactions with medications needed for travel? and 5) how will they monitor their anticoagulation while traveling? Knowing the answers to these questions then can allow for proper counseling and planning for the anticoagulated traveler's trip.

By virtue of their religious principles, Jehovah's Witnesses (JWs) generally object to receiving blood products, raising numerous ethical, legal, and medical challenges for providers who care for these patients, especially in the emergent setting. In this review, we discuss several areas relevant to the care of JWs, including the current literature on "bloodless" medical care in the setting of perioperative and intraoperative management, acute blood loss, trauma, pregnancy, and malignancy. We have found that medical and administrative efforts in the form of bloodless medicine and surgery programs can be instrumental in helping to reduce risks of morbidity and mortality in these patients. Planning prior to an anticipated event associated with blood loss or anemia (such as elective surgery, pregnancy, and chemotherapy) is critical. Specifically, bloodless medicine programs should prioritize vigilant early screening and management of anemias, early establishment of patient wishes regarding transfusion, and the incorporation of those wishes into multidisciplinary medical and surgical care. Although there are now a variety of human-based and nonhuman-based products available as transfusion alternatives, the degree and quality of evidence to support their use varies significantly between products and is also largely dependent on the clinical setting.