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Jonathan C Roberts,1 Annette von Drygalski,2 Jenny Y Zhou,2 George M Rodgers,3 Kristin Ansteatt,1 Michael D Tarantino1 1Bleeding & Clotting Disorders Institute, University of Illinois College of Medicine – Peoria, Peoria, IL, USA; 2Hemophilia and Thrombosis Treatment Center, University of California at San Diego, San Diego, CA, USA; 3Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USACorrespondence: Michael D Tarantino, The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine – Peoria, 427 West Northmoor Road, Peoria, IL, 61614, USA, Tel +1 309-692-5337, Email mtarantino@ilbcdi.orgAbstract: Hereditary antithrombin deficiency (ATD) is a rare autosomal dominant condition (estimated prevalence 1:500– 1:5000). Most ATD patients have AT activity levels 40– 60% of normal. We present treatments for venous thromboembolism (VTE) in five cases of hereditary ATD. Four patients had a family history of ATD, and one had a de novo mutation. The majority of patients had a VTE while on prophylactic anticoagulation. AT concentrate augmentation was added in these cases to treat the VTE and for prophylaxis against further episodes. Two patients had significant bleeding events, one had permanent physical sequelae. Two of the patients were pregnant. VTE is a common cause of morbidity and mortality during pregnancy. Although low molecular weight heparins are the drugs of choice during pregnancy, this treatment was inadequate in one patient (developed VTE on therapy). These cases emphasize the need to screen for ATD in young patients (< 55 years) presenting with VTE. AT augmentation therapy may be necessary in patients inadequately treated with conventional anticoagulants. Careful monitoring and individualized care are needed in ATD patients, especially those with demonstrated bleeding tendencies.Keywords: clotting disorders, venous thromboembolism, anticoagulation, bleeding tendencies

George M Rodgers,1 Misa Berndt,2 Megan Fonteno,3 Jeffrey A Gilreath2,4 1Division of Hematology and Hematologic Malignancies Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA; 2Sugarhouse Hematology, University of Utah, Salt Lake City, UT, USA; 3Clinical Pharmacy, MD Anderson Cancer Institute, Houston, TX, USA; 4Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, UT, USACorrespondence: George M Rodgers, Division of Hematology and Hematologic Malignancies, University of Utah Medical Center, Salt Lake City, UT, 84132, USA, Tel +1 801-213-2076, Email George.rodgers@hsc.utah.eduAbstract: We describe a case of refractory thrombotic thrombocytopenic purpura (7 lines of therapy) in which caplacizumab was used over a 6-month period as rescue therapy. Caplacizumab maintained the patient in clinical remission until successful immunosuppression was achieved resulting in normal ADAMTS13 levels. This case illustrates the utility of caplacizumab therapy in treating refractory TTP.Keywords: thrombotic thrombocytopenic purpura, caplac izumab, ADAMTS13, von Willebrand factor

Background: ADAMTS13 is the enzyme responsible for cleaving ultra-large von Willebrand factor (vFW) multimers. Commercial kits have been recently developed that use a fluorescence resonance energy transfer (FRET) methodology to measure ADAMTS13 activity. Methods: In this study, we compared the results from 2 recently released commercial kits (GTI and Technoclone) with results obtained from a reference laboratory also using FRET technology to assay samples from patients referred for a possible diagnosis of thrombotic thrombocytopenic purpura (TTP). Results: A total of 29 samples were assayed and compared. Six samples had less than 5% of normal ADAMTS13 activity identified by the reference laboratory. The GTI kit identified only 4 of these 6 samples, while the Technoclone kit identified all 6. Conclusion: The results of this study demonstrate that commercial ADAMTS13 activity assays currently available are clinically useful in diagnosing TTP. [ABSTRACT FROM AUTHOR]

We compared the BD standard glass sodium citrate Vacutainer to the BD plastic sodium citrate Vacutainer, evaluating 19 esoteric coagulation analytes, including comparisons, mean, and standard deviation for 20 normal donor plasma samples.Only 1 analyte, the thrombin time, was found to vary depending on the collection tube used.Laboratories should establish separate reference intervals for plastic and glass Vacutainers for the thrombin time assay. Other esoteric coagulation analytes do not need separate reference intervals. [ABSTRACT FROM AUTHOR]

Introduction: Numerous clinical trials affirm the efficacy and safety of IV iron to treat cancer-related anemia (CRA). Nonetheless, evaluation and treatment of CRA remains suboptimal., Areas Covered: This review summarizes CRA therapy with a focus on iron deficiency and its treatment. The literature search was conducted using the National Library of Medicine (PubMed) database from 2004 to 2024. Topics reviewed include CRA pathophysiology, laboratory diagnosis of iron deficiency, a summary of clinical trial results using IV iron to treat CRA, and safety aspects., Expert Opinion: Despite overwhelming positive efficacy and safety data, IV iron remains underutilized to treat CRA. This is likely due to persistent (unfounded) concerns about IV iron safety and lack of physician awareness of newer clinical trial data. This leads to poor patient quality of life and patient exposure to anemia treatments that have greater safety risks than IV iron. Solutions to this problem include increased educational efforts and considering alternative treatment models in which other providers separately manage CRA. The recent availability of new oral iron therapy products that are effective in treating anemia of inflammation has the potential to dramatically simplify the treatment of CRA.

Introduction: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels., Aims: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre., Methods: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected., Results: Forty-seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty-one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self-reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported., Conclusion: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non-VWD population., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit., Competing Interests: Declaration of Conflicting InterestsThe authors disclose support for the present manuscript in the form of medical writing and article processing charges, funded by Grifols, Inc. Dr Rodgers discloses membership on a jury panel sponsored by Grifols, Inc., that reviews research grant proposals on antithrombin research.

Background: Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management., Methods: We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS-MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted., Objectives: To describe the clinical presentation and outcomes of different therapeutic approaches., Results: Seventy-five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity <30 IU/dL (86.6%) and factor VIII levels <50 IU/dL (91.8%). Bleeding severity ranged from no bleeding (16.1%) to minor bleeding (46.4%) and major bleeding (37.5%). The overall clinical success rates for 1-deamino-8-D-arginine vasopressin (DDAVP), factor replacement therapy, and intravenous immunoglobulin (IVIG) were 43.8%, 33.3%, and 85.4%, respectively. The laboratory response rates for DDAVP, factor replacement therapy, and IVIG were 39.0%, 62.9%, and 88.6%, respectively. Several other treatments were also reported in small numbers, out of which myeloma-directed therapies, plasma exchange, recombinant factor VIIa, and antifibrinolytics appeared most successful, while immunosuppressive agents were largely ineffective., Conclusion: IVIG appears to be an effective treatment for AVWS-MGUS bleeding, conferring a high clinical success rate with measurable laboratory outcomes; albeit temporary. DDAVP and factor replacement therapy may be partially successful in controlling minor bleeds, but not major bleeds. Other less commonly used agents may be effective in certain cases, although data are limited., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

: The objectives of this study were firstly to determine the prevalence of overweight/obesity in adult persons with hemophilia in Utah, and to explore the association between age, disease severity and race with body mass index (BMI), and secondly to provide recent data on the prevalence of overweight/obesity in the hemophilia population via a review of the literature. We conducted a retrospective cross section study of adult persons with hemophilia who were seen at a Utah hemophilia treatment center from 1 January 2017 to 31 December 2019. The electronic database PubMed was searched for studies with observation periods from 1 January 2012 to 31 December 2019. The age-adjusted prevalence for overweight/obesity in the adult Utah hemophilia population was higher than the overall Utah population and the general US population. After adjusting for race and age, mild hemophilia was associated with a 7.7% higher BMI (95% confidence interval, 0.023-15.98%, P < 0.05). Review of the literature demonstrated high levels of overweight/obesity in hemophilia communities globally with considerable heterogeneity between studies. Despite increasing awareness, prevalence of overweight/obesity in the hemophilia population remains high in comparison with the general population. There is a critical need to address this issue acutely at hemophilia treatment centers due to the considerable burden of obesity.

Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia., (© 2020 by The American Society of Hematology.)

Purpose: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache., Methods: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members., Results: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis., Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits unique properties as a biological marker of hemostatic abnormalities as well as an indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this, the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly, D-dimer has been extensively investigated for excluding the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and for monitoring other conditions in which the patient is at high risk of bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization., (© 2019 Wiley Periodicals, Inc.)

Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration. Therefore, continuous weekly dosing of romiplostim despite platelet count being above 400k/µL combined with twice weekly vigilant monitoring is an alternative method of romiplostim dosing that mitigates severe fluctuations in platelets. We also discuss important details, postulated mechanisms, and evidence-based mitigation strategies.

Anemia is common in patients with cancer or with chronic kidney disease (CKD). Although the introduction of erythropoiesis-stimulating agents (ESAs) has transformed the management of anemia, their use has been complicated by a number of factors including frequent guideline updates, safety concerns and, in the United States, a Risk Evaluation and Mitigation Strategy (REMS) program, which aimed to ensure that the benefits of ESAs outweigh the risks. Many previous concerns around ESA use in cancer and CKD have been addressed by the reassuring results of post-approval studies, and biosimilar ESAs have been used in Europe for many years, with safety and efficacy profiles similar to originator products. This review describes the evolution of the use of ESAs from approval to the present day, discussing results from clinical studies of ESAs in cancer and CKD, and the influence of these findings on product labeling and guideline updates. We also discuss the impact of the introduction of ESA biosimilars in Europe, bringing cost savings and increased access to patients.

Cancer-related anemia (CRA) is a commonly occurring problem for patients with cancer regardless of whether they are receiving treatment with chemotherapy or immunotherapy. It may result from one or more processes (decreased production, increased destruction, or increased loss of red blood cells, RBC). Perturbations in iron availability form the primary basis for anemia in many patients with cancer-related anemia. Functional iron deficiency (FID) anemia is a condition in which the patient has adequate or increased iron stores, but this iron pool is not available for erythropoiesis. Erythropoiesis-stimulating agents (ESAs) were the original treatment for FID; over time, however, if the supply of iron cannot keep pace with increased RBC synthesis driven by ESAs, FID may eventually lead to the lack or loss of ESA responsiveness. Subsequent clinical trials reported that intravenous (IV) iron could enhance the erythropoietic response to ESAs. This chapter reviews the pathogenesis of FID and summarizes the literature on the treatment of cancer- and chemotherapy-induced anemia. Clinical trials using IV iron with or without ESAs are reviewed in addition to the currently available IV iron products. The consensus conclusions from these trials, as well as guideline recommendations, support the use of IV iron in these patients to enhance ESA responsiveness, decrease ESA dosage, and reduce RBC transfusions. Little data have been published on the long-term safety of IV iron or its impact on tumor growth. This paper also briefly explores novel approaches for the treatment of FID anemia, which has relevance in treating not only cancer patients but also patients with benign inflammatory disorders., (© 2019 S. Karger AG, Basel.)

Introduction: Evaluation of von Willebrand factor (VWF) multimeric distribution is useful for subclassification of von Willebrand disease (VWD). Multimer analysis has historically been a manual, labor-intensive laboratory-developed test. The first commercial method for multimeric analysis was recently developed that utilizes a single instrument for gel electrophoresis, staining, and densitometry. The current study was undertaken to evaluate the performance characteristics of the new commercial method., Methods: Studies performed with the commercial method included evaluation of accuracy (method comparison), reference intervals (establishment of normal migration patterns in normal donor specimens), precision (multimer pattern reproducibility), and analytical sensitivity., Results: In the method comparison studies, concordant interpretations were obtained in 19 of 24 comparisons, including normal and abnormal specimens. The 5 specimens with discordant interpretations all involved slight differences and none were considered clinically significant. Thirty-eight normal donor specimens demonstrated normal multimer patterns. Multimer pattern reproducibility was demonstrated in normal and abnormal controls tested on each gel. In the sensitivity studies, adequate visualization of multimers was determined to require VWF protein concentrations of approximately 5%-10% of normal., Conclusion: The commercial multimer method is a streamlined test that demonstrates comparable performance characteristics to our current laboratory-developed method and that provides the advantage of both electrophoresis gels and densitometry scans to aid interpretation., (© 2018 John Wiley & Sons Ltd.)

Normal hemostasis provides for balanced interactions between the blood vessel wall, coagulation proteins, and platelets. After vascular injury, primary hemostasis and secondary hemostasis function in a coordinated fashion to stop bleeding. Standard coagulation tests have been shown in multiple studies to predict bleeding and mortality in neurosurgical patients. Emerging coagulation tests are useful point-of-care assays that guide transfusion therapy and diagnose patients with hyperfibrinolysis. This article provides an overview of hemostasis, a summary of standard coagulation testing and point-of-care tests, and a brief review of coagulation test usefulness in neurosurgery, focusing on studies in patients with traumatic brain injury., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a zinc-containing metalloprotease that cleaves von Willebrand factor (vWf). Previous publications by our laboratory have shown that ADAMTS-13 may also be involved in angiogenesis. For this study, we report the successful transient knockdown of endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) via siRNA and the effects of reduced endogenous ADAMTS-13 on HUVEC angiogenesis functions. 15nM of ADAMTS-13 siRNA reduced HUVEC ADAMTS-13 protein levels by 90% after 24h incubation, whereas control siRNA did not affect endogenous ADAMTS-13 levels. Furthermore, this transfection did not affect the HUVEC endogenous protein level of ADAMTS-1, a related family member of ADAMTS-13 indicating the specificity of the siRNA. Transfection of HUVEC with 15nM of ADAMTS-13 siRNA resulted in a 21% decrease in proliferation after 24h incubation. The effects of ADAMTS-13 knockdown on migration of HUVEC across a scratch wound were also evaluated. 24h after transfection with control siRNA, there was increased cell migration across the scratch wound. This dramatic migration did not occur with ADAMTS-13 knockdown cells. Decreased protein levels of endogenous ADAMTS-13 also affected angiogenesis as measured by endothelial cell tube formation using a Matrigel matrix method. The tube lengths, sizes and junction numbers of the ADAMTS-13 knockdown cells were all significantly lower compared to control cells by about 40%. The protein level of vascular endothelial growth factor (VEGF), a well-known regulator of angiogenesis, was significantly decreased by 45% upon knockdown of ADAMTS-13. Moreover, activity of the AKT pathway, one of the VEGF angiogenesis downstream signaling pathways was down-regulated by ADAMTS-13 siRNA. These data indicate that in cultured endothelial cells, one role of endogenous ADAMTS-13 is regulation of angiogenesis, mediated through VEGF and AKT signaling pathway. Overall, our data suggest an additional model of endogenous ADAMTS-13 functionality, beyond that of cleaving von Willebrand factor., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Portal vein thrombosis (PVT) is a serious problem with a high morbidity and mortality, often exceeding 40% of affected patients. Recently, PVT has been reported in patients after laparoscopic sleeve gastrectomy (LSG). The frequency is surprisingly high compared with other abdominal operations., Objective: We present a series of 5 patients with PVT after LSG. The treatment was not restricted simply to anticoagulation alone, but was determined by the extent of disease. A distinction is made among nonocclusive, high-grade nonocclusive, and occlusive PVT. We present evidence that systemic anticoagulation is insufficient in occlusive thrombosis and may also be insufficient in high-grade nonocclusive disease., Setting: Single private institution, United States., Methods: We present a retrospective analysis of 646 patients who underwent LSG between 2012 and 2015. In all patients, the diagnosis was established with an abdominal computed tomography (CT) scan as well as duplex ultrasound of the portal venous system. All patients received systemic anticoagulation. Depending on the extent of disease, thrombolytic therapy and portal vein thrombectomy were utilized. All patients received long-term anticoagulation., Results: Four patients with PVT were identified. A fifth patient with PVT after LSG was referred from another center. The mean age of all patients was 49 years. One patient had a history of deep vein thrombosis (DVT). No complications were identified intraoperatively or during the hospital stay, and all patients were discharged by postoperative day 2. The patients presented with PVT at an average of 20 days (range: 10-35) post-LSG. The CT scan was positive for PVT in all patients. In stable noncirrhotic patients with nonocclusive disease, we administered therapeutic anticoagulation. One patient with high-grade, nonocclusive PVT received anticoagulation alone. Patients with occlusive disease were treated with operative thrombectomy including intraoperative and postoperative thrombolysis (tissue plasminogen activator) with subsequent therapeutic anticoagulation, followed by oral warfarin or a factor Xa inhibitor. There was 1 death from multisystem organ failure in the patient who was referred from another institution with occlusive disease, initially managed only with an anticoagulation infusion., Conclusions: We maintain that portal vein patency is essential to normal gastrointestinal physiology and should be the treatment goal in all patients with PVT. In these patients, the therapeutic option should be guided by the extent of the thrombosis. In view of currently available approaches, we propose that operative portal vein thrombectomy, in conjunction with fibrinolysis and anticoagulation, offers the best long-term success in patients with occlusive PVT., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The ability to change coloration allows animals to modify their patterning to suit a specific function. Many freshwater fishes, for example, can appear cryptic by altering the dispersion of melanin pigment in the skin to match the visual background. However, melanin-based pigments are also used to signal dominance among competing males; thus colour change for background matching may conflict with colour change for social status signalling. We used a colour-changing freshwater fish to investigate whether colour change for background matching influenced aggressive interactions between rival males. Subordinate males that had recently darkened their skin for background matching received heightened aggression from dominant males, relative to males whose coloration had not changed. We then determined whether the social status of a rival male, the focal male's previous social status, and his previous skin coloration, affected a male's ability to change colour for background matching. Social status influenced skin darkening in the first social encounter, with dominant males darkening more than subordinate males, but there was no effect of social status on colour change in the second social encounter. We also found that the extent of skin colour change (by both dominant and subordinate males) was dependent on previous skin coloration, with dark males displaying a smaller change in coloration than pale males. Our findings suggest that skin darkening for background matching imposes a significant social cost on subordinate males in terms of increased aggression. We also suggest that the use of melanin-based signals during social encounters can impede subsequent changes in skin coloration for other functions, such as skin darkening for background matching.

Demographic rates are shaped by the interaction of past and current environments that individuals in a population experience. Past environments shape individual states via selection and plasticity, and fitness-related traits (e.g. individual size) are commonly used in demographic analyses to represent the effect of past environments on demographic rates. We quantified how well the size of individuals captures the effects of a population's past and current environments on demographic rates in a well-studied experimental system of soil mites. We decomposed these interrelated sources of variation with a novel method of multiple regression that is useful for understanding nonlinear relationships between responses and multicollinear explanatory variables. We graphically present the results using area-proportional Venn diagrams. Our novel method was developed by combining existing methods and expanding upon them. We showed that the strength of size as a proxy for the past environment varied widely among vital rates. For instance, in this organism with an income breeding life history, the environment had more effect on reproduction than individual size, but with substantial overlap indicating that size encompassed some of the effects of the past environment on fecundity. This demonstrates that the strength of size as a proxy for the past environment can vary widely among life-history processes within a species, and this variation should be taken into consideration in trait-based demographic or individual-based approaches that focus on phenotypic traits as state variables. Furthermore, the strength of a proxy will depend on what state variable(s) and what demographic rate is being examined; that is, different measures of body size (e.g. length, volume, mass, fat stores) will be better or worse proxies for various life-history processes., (© 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.)

Introduction: The serotonin release assay (SRA) is considered the gold standard laboratory test for heparin-induced thrombocytopenia (HIT). The historic SRA method uses platelets loaded with radiolabeled serotonin to evaluate platelet activation by HIT immune complexes. However, a nonradioactive method is desirable. We report the performance characteristics of a high-performance liquid chromatography (HPLC) SRA method., Methods: We validated the performance characteristics of an HPLC-SRA method, including correlation with a reference laboratory using the radioactive method. Serotonin released from reagent platelets was quantified by HPLC using fluorescent detection. Results were expressed as % release and classified as positive, negative, or indeterminate based on previously published cutoffs., Results: Serum samples from 250 subjects with suspected HIT were tested in the HPLC-SRA and with the radioactive method. Concordant classifications were observed in 230 samples (92%). Sera from 41 healthy individuals tested negative. Between-run imprecision studies showed standard deviation of <6 (% release) for positive, weak positive, and negative serum pools. Stability studies demonstrated stability after two freeze-thaw cycles or up to a week of refrigeration., Conclusion: The HPLC-SRA has robust performance characteristics, equivalent to the historic radioactive method, but avoids the complexities of working with radioactivity., (© 2015 John Wiley & Sons Ltd.)

Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa., Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF)., Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability., Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity., Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered., (© 2015 International Society on Thrombosis and Haemostasis.)

Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. The goals of this study were to understand the angiogenic pathways ADAMTS13 activates and to identify the important structural components of ADAMTS13 that stimulate angiogenesis. Incubation of human umbilical vein endothelial cells (HUVEC) with 150 ng/mL (1 nM) of recombinant human ADAMTS13 induced VEGF expression by 53 % and increased VEGF mRNA by over sixfold, both within 10 min; the measured VEGF levels steadily decreased over 2 h, as shown by Western blot and ELISA. Phosphorylation of VEGFR2 was significantly enhanced in HUVEC after incubation with ADAMTS13 (1 nM). Structure-function analysis showed that an ADAMTS13 variant containing thrombospondin type 1 (TSP1) 2-8 repeats (TSP1 2-8), TSP1 2-8 plus CUB domains (TSP1 2-8 plus CUB), or TSP1 5-8 repeats plus CUB domains (TSP1 5-8 plus CUB) increased HUVEC proliferation by 41-54 % as compared to the EBM-2 controls. Chemotaxis assays further demonstrated that the TSP1 domains of ADAMTS13 increased HUVEC migration by 2.65-fold. Incubation of HUVEC with both ADAMTS13 variants containing TSP1 repeats and anti-VEGF IgG abrogated the enhanced effect of ADAMTS13 on proliferation, migration, and VEGFR2 phosphorylation. In conclusion, ADAMTS13-induced endothelial cell angiogenesis occurs via the upregulation of VEGF and phosphorylation of VEGFR2. This angiogenic activity depends on the C-terminal TSP1 repeats of ADAMTS13.

Cancer-related anemia (CRA) is due to multiple etiologies, including chemotherapy-induced myelosuppression, blood loss, functional iron deficiency, erythropoietin deficiency due to renal disease, marrow involvement with tumor as well as other factors. The most common treatment options for CRA include iron therapy, erythropoietic-stimulating agents (ESAs), and red cell transfusion. Safety concerns as well as restrictions and reimbursement issues surrounding ESA therapy for CRA have resulted in suboptimal treatment. Similarly, many clinicians are not familiar or comfortable using intravenous iron products to treat functional iron deficiency associated with CRA. This article summarizes our approach to treating CRA and discusses commonly encountered clinical scenarios for which current clinical guidelines do not apply., (Copyright © 2013 Wiley Periodicals, Inc.)

Background and Objectives: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare, clinically diagnosed disorder characterized by widespread intravascular platelet thrombosis. The pathophysiology involves acquired deficiency of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats), the enzyme responsible for cleavage of high molecular weight vonWillebrand factor multimers. Disease mortality is high, although prompt treatment with plasma exchange is generally effective. A readily available and highly reliable method of identifying ADAMTS13-deficient patients for appropriate plasma exchange is therefore of interest., Materials and Methods: Our initial study involved the assessment of multiple clinical and laboratory variables in patients with clinically suspected TTP for whom ADAMTS13 assay was performed. Five variables were found to be of significant predictive power. This enabled the development of a point-based scoring system to efficiently determine the likelihood of TTP and response to plasma exchange in a given patient. This current study involved a separate validation cohort of patients with clinically suspected TTP who underwent ADAMTS13 testing within two large healthcare systems in Utah between 2009 and 2011. The previously derived score was applied to this cohort and its performance was analysed. Additionally, the original and validation cohorts were combined to revisit the predictive power of individual variables and the five-variable prediction score., Results: A total of 84 (11 paediatric cases excluded) patients comprised the validation population. The percentage of TTP diagnoses in this group (10%) was identical to that in the initial cohort. Using an ADAMTS13 activity of <10% of normal, our original score correctly predicted or excluded severe ADAMTS13 deficiency in all patients in the second cohort when data for all variables was available. Individual variables retained predictive power and the performance of a three-variable parsimonious model, as well as the ultimate diagnoses for patients in the second cohort are described., Conclusion: This work confirms the predictive power of a simple point-based score to exclude TTP as evidenced by severe ADAMTS13 deficiency in appropriately selected patients. It may enable clinicians to rapidly begin plasma exchange or to pursue an alternative cause of thrombotic microangiopathy., (© 2013 International Society of Blood Transfusion.)

Objectives: Elevations of factor IX (FIX) are thought to contribute to thrombotic risk, but this has not been well characterized. We retrospectively sought to determine whether elevated FIX levels are a risk factor for thrombosis in 81 adult subjects younger than 65 years (mean, 47 years) who were referred for evaluation of a hypercoagulable state., Methods: Patients were classified by arterial transient ischemic attack/stroke (TIA/stroke, n = 62) or venous thromboembolism (VTE, n = 19) events. FIX activity testing was performed on all 81 subjects and a reference group of 40 healthy individuals., Results: Thirteen (21%) of 62 subjects with TIA/stroke and 5 (26%) of 19 subjects with VTE had elevated FIX activity. Odds ratios for TIA/stroke and VTE in subjects with elevated FIX activity were 3.7 (95% confidence interval [CI], 0.76-17.65) and 6.8 (95% CI, 1.18-39.07), respectively., Conclusions: Our findings suggest an association between elevated FIX levels and both arterial and venous thrombotic events.

Many animals, particularly reptiles, amphibians, fish and cephalopods, have the ability to change their body colour, for functions including thermoregulation, signalling and predator avoidance. Many fish plastically darken their body colouration in response to dark visual backgrounds, and this functions to reduce predation risk. Here, we tested the hypotheses that colour change in fish (1) carries with it an energetic cost and (2) affects subsequent shoal and habitat choice decisions. We demonstrate that guppies (Poecilia reticulata) change colour in response to dark and light visual backgrounds, and that doing so carries an energetic cost in terms of food consumption. By increasing food intake, however, guppies are able to maintain growth rates and meet the energetic costs of changing colour. Following colour change, fish preferentially choose habitats and shoals that match their own body colouration, and maximise crypsis, thus avoiding the need for further colour change but also potentially paying an opportunity cost associated with restriction to particular habitats and social associates. Thus, colour change to match the background is complemented by behavioural strategies, which should act to maximise fitness in variable environments.

Aggregations of different-looking animals are frequently seen in nature, despite well-documented selection pressures on individuals to maintain phenotypically homogenous groups. Two well-known theories, the 'confusion effect' (reduced ability of a predator to accurately target an individual in a group) and the 'oddity effect' (preferential targeting of phenotypically distinct, 'odd', individuals) act together to predict the evolution of behaviours in prey that lead to groups of animals that are homogeneous in appearance. In contrast, a recently proposed mechanism suggests that mixed groups could be maintained if one species in a mixed group is more conspicuous against the habitat than the other, as confusion effects generated by the conspicuous species impede predator targeting of the cryptic species; thus, cryptic species benefit from association with conspicuous ones. We test these contrasting predictions from the perspective of both predators and prey, and show that cryptic individual Daphnia are at reduced risk of predation from three-spine sticklebacks Gasterosteus aculeatus when in mixed-phenotype groups, a risk that is reduced further as the number of conspicuous individuals increases, supporting the hypothesis for the evolution of mixed groups. In contrast, while the preference for associating with colour-matched conspecifics by mollies (Poecilia sphenops) was reduced when they were cryptic, we found no evidence for active association with conspicuous conspecifics. We conclude that prey animals must balance the relative risks of oddity and conspicuousness in their social decisions, and that this could potentially lead to the evolution of mixed-phenotype grouping as a response to predation risk alone.