Juliana Perez Botero

Incidence of symptomatic venous thromboembolism in patients with hemophilia undergoing joint replacement surgery: A retrospective study

INTRODUCTION Venous thromboembolism (VTE) is a recognized complication after joint replacement surgery, and prophylaxis is routinely used in patients without bleeding disorders. However, for patients with hemophilia, pharmacologic prophylaxis is highly variable and controversial because of the inherent bleeding risk. AIM To review our institutional experience with outcomes of total knee or hip arthroplasty with regard to symptomatic VTE and use of VTE prophylaxis in patients with hemophilia and without inhibitors. METHODS We reviewed records of 42 consecutive patients with hemophilia A or B who underwent 71 hip or knee replacements over a 39-year period. We also reviewed the literature to estimate the incidence of VTE after arthroplasty in the hemophilia population. RESULTS All patients used compression stockings for up to 6weeks after surgery; additionally, 6 cases (10.5%; 57 with available data) used sequential intermittent compression devices and 2 (2.8%) postoperatively received low-molecular-weight heparin. One patient (1.4%) who received low-molecular-weight heparin had a symptomatic, lower-extremity, deep venous thrombosis 10days after hip replacement for traumatic fracture. None of the other 70 surgical cases had symptomatic VTE within 3months after the procedure. Analysis of pooled data from published series of hemophilia patients undergoing arthroplasty showed an estimated incidence of symptomatic VTE of 0.5%. CONCLUSION Our study suggests that in patients with hemophilia, joint replacement surgery can be performed safely without routine pharmacologic VTE prophylaxis and without increasing risk of thromboembolic events. Pharmacologic VTE prophylaxis may be considered in select patients with known additional risk factors for VTE.

Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group

Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management.

Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family.

Abstract The clinical and laboratory characteristics of patients with non-syndromic, autosomal dominant thrombocytopenia secondary to germ line ANKRD26 mutations appear to be heterogeneous. Except for a targeted molecular genotyping approach, there is no distinct clinical or laboratory phenotype that has been specifically associated with this particular gene mutation. Such heterogeneity could be due to variations in mutation and genetic background in different families. To understand the phenotypic heterogeneity, we thoroughly studied one affected family using the International Society for Thrombosis and Haemostasis bleeding assessment tool and both clinically validated standard and esoteric platelet testing (electron microscopy (EM) and flow cytometry). We found that decreased platelet aggregation with arachidonic acid and epinephrine agonists was common in affected family members. EM studies demonstrated persistent borderline low mean dense granules per platelet, decreased alpha granules and an increased canalicular network pattern in all affected members. Since these characteristics are subtle or non-pathognomonic, molecular testing for ANKRD26 mutation remains the most reliable test to render a diagnosis and should be considered when evaluating a patient or family with congenital thrombocytopenia, particularly if there is a history of myeloid neoplasms.

Refractory bleeding from intestinal angiodysplasias successfully treated with danazol in three patients with von Willebrand disease.

von Willebrand disease (VWD) is associated with development of gastrointestinal (GI) vascular malformations that lead to chronic GI bleeding. Conventional management, including von Willebrand factor concentrate replacement and endoscopic ablation or bowel resection, does not consistently reduce hemorrhage. We describe three patients with VWD for whom conventional management failed to control GI bleeding. We retrospectively reviewed medical records of patients with VWD and GI bleeding. After patients began treatment with danazol, we observed long-term reductions in GI bleeding and packed red blood cell transfusion requirements. One patient had severe liver toxicity and was found to have concomitant primary biliary cirrhosis. Danazol use may be considered in patients with VWD and GI bleeding due to angiodysplasia that otherwise fails to respond to conventional treatment; the primary aim of treatment is to reduce transfusion dependence. The benefits are variable and possibly transient. Monitoring for toxicity is important when this treatment is pursued.

Clinical characteristics and platelet phenotype in a family with RUNX1 mutated thrombocytopenia

Juliana Perez Botero, Dong Chen, Margot A. Cousin, Julie A. Majerus, Lea M. Coon, Teresa M. Kruisselbrink, Eric W. Klee, Konstantinos N. Lazaridis, Rajiv K. Pruthi and Mrinal M. Patnaik Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Special Coagulation Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center for Individualized Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Genetics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

Capturing and Incorporating Patient-Reported Outcomes into Clinical Trials: Practical Considerations for Clinicians.

Patient centeredness as the focus of healthcare delivery requires the incorporation of patient-reported outcomes into clinical trials. Clearly defining measurable outcomes as well as selecting the most appropriate validated collection tool to use is imperative for success. Creating and validating one’s own instrument is also possible, albeit more cumbersome. Meticulous data collection to avoid missing data is key, as is limiting the number of data collection points to prevent survey fatigue and using electronic systems to facilitate data gathering and analysis. Working in a multidisciplinary team that includes statisticians with expertise in patient reported outcomes is essential to navigate the complexities of statistical analysis of these variables. Use of available and emerging technologies for data collection and analysis as well as data sharing will greatly facilitate the process of incorporating patient-reported outcomes into trials and routine clinical practice.

Factor IX Gene (F9) Genotyping Trends and Spectrum of Mutations Identified: A Reference Laboratory Experience

&NA; In hemophilia B (HB), factor IX gene (F9) genotyping is used for molecular confirmation of affected individuals, for carrier testing, to facilitate the identification of those at risk for anaphylaxis/inhibitors (associated with large deletions), and to assist in assigning disease severity. Owing to test costs, optimal test utilization involves pre/post‐test counseling and appropriate patient and test selection (e.g., mutation screening [F9 MS] vs. known mutation [F9 KM] testing). This article aims to review the trends and outcomes of F9 ‐genotyping orders and describe the spectrum of variants identified in a sample of individuals in our reference laboratory. We performed a retrospective review of consecutive orders submitted to the Special Coagulation DNA Diagnostic Laboratory, Mayo Clinic, between 2012 and 2015. A total of 133 orders (38%) were identified for men: 118 (88%) were F9 MS and 15 (12%) were F9 KM. Thirteen orders (10%) were cancelled. A total of 209 orders were identified for women: 178 (85%) were F9 MS and 31 (15%) were F9 KM. Thirty‐seven orders (18%) were cancelled and 30% of the tests performed yielded negative results. A total of 164 samples (47%) were received without clinical information. Seventeen previously unreported variants were identified. F9 genotyping provides useful information for HB management; however, 18% of our orders were cancelled and almost half were received without relevant clinical information, thus reaffirming the need for ongoing scrutiny of submitted orders. Optimal patient and test selection is important as is the accurate interpretation of variants identified. Most of the pathogenic variants identified were point mutations, with very few large deletions, consistent with the literature.

Primary Lymphedema and Viral Warts in GATA2 Haploinsufficiency

A 9-year-old boy presented with viral warts (Figure 1) since age 3 years, lymphedema (Figure 2), and neutropenia. His sister and paternal aunt also had generalized warts. Their father was diagnosed with acute myeloid leukemia (AML) at age 37 years, and the paternal grandfather had died of acute leukemia. 1339A>C, p.S447R mutation in GATA2 leading to haploinsuffiency was subsequently identified. Emberger syndrome (congenital lymphedema) and viral warts are part of the GATA2 mutated disorders, which also include familial AML and myelodysplastic syndrome, chronic neutropenia, monocytopenia, and Mycobacterium avium complex infections. Features of myelodysplasia can be seen at an early age. Pelger Huët like cells (Supplemental Figure, available online at http://www.mayoclinicproceedings. org)dbilobed neutrophils from ineffective hematopoiesisdwere identified in the patient’s 31-year-old aunt. The patient’s bone marrow was hypocellular but with normal morphology at diagnosis. Because of the high risk of AML, he underwent matched unrelated donor allogeneic transplantation.

von Willebrand disease type1/type 2N compound heterozygotes: diagnostic and management challenges.

Keywords: von Willebrand disease; von Willebrand factor; factor VIII; bleeding; genetics of thrombosis and haemostasis

Practice patterns in the diagnosis of inherited platelet disorders within a single institution.

&NA; The diagnosis of inherited platelet disorders (IPDs) is challenging with variable diagnostic practices existing between institutions. To determine patterns and utility of diagnostic testing practices for IPDs within a single institution, a retrospective cohort study was performed. Records of 50 patients (50% women), median age 32 years (1 day to 81 years) were analyzed. In total, 28 (53%) had a positive International Society of Thrombosis and Hemostasis Bleeding Assessment Tool score. Test-ordering patterns were highly variable. All patients had platelet morphology analysis by light microscopy. In total, 42 (84%) underwent light transmission aggregometry, 43 (86%) platelet function analyzer, 37 (74%) platelet electron microscopy, 25 (50%) flow cytometry, and 15 (30%) genetic testing. Platelet function analyzer and light transmission aggregometry were always used as first-order tests, followed by platelet transmission electron microscopy and flow cytometry (81 and 84%, respectively). Genetic testing was obtained up front in five cases (33% of orders), mostly in patients with syndromic thrombocytopenia or in the setting of a known genetic disorder. Test-ordering practices did not adhere to published algorithms. Even within a single institution, great heterogeneity exists in the testing approach to IPDs. Although, a large proportion of cases were studied with platelet transmission electron microscopy and flow cytometry, standard platelet assays established the diagnosis in a great majority. Standardization of testing practices, first beginning at the institutional level is a much needed step forward.