Catherine P M Hayward

McMaster University, Hamilton, Ontario, Canada

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Publications (118)626.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Although rare, the prevalence of inherited platelet function disorders (IPFD) is probably underestimated due to underdiagnosis [1]. IPFD are heterogeneous in severity, mechanisms, and frequency and few are characterized at the molecular level. While severe IPFD, like Glanzmann Thrombasthenia (GT) or Bernard-Soulier Syndrome (BSS), are now rather straightforward to identify, the diagnosis of most other forms is cumbersome and requires complex assaysThis article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 11/2014; · 6.08 Impact Factor
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    ABSTRACT: IntroductionThe development of an automated, von Willebrand factor (VWF) activity assay, Innovance® VWF Ac (VWF:Ac), which measures VWF binding to the platelet receptor glycoprotein Ibα without ristocetin, led us to evaluate the assay for diagnosing von Willebrand disease (VWD) and monitoring therapy.Methods After validating that the assay could be performed on an instrument from a different manufacturer, we compared VWF:Ac to VWF ristocetin cofactor activity (VWF:RCo) findings, including ratios of activity/antigen, for 100 healthy controls and 262 consecutive clinical samples from 217 patients (197 adults, 64 children, n = 1 age unknown) referred for VWF testing.ResultsThere was excellent correlation (R2 = 0.96) between VWF:Ac results run at two different sites on two different instruments. VWF:Ac had greater precision and sensitivity to low levels of VWF than the VWF:RCo method. Although there was good correlation between VWF:Ac and VWF:RCo results among healthy controls and patient subjects, VWF:Ac results were undetectable and/or significantly lower than VWF:RCo among patients who had types 2A, 2B, or 2M VWD. Additionally, a higher proportion of patient samples were classified as showing qualitative defects using the VWF:Ac compared with VWF:RCo method. While most samples drawn on VWD therapy had similar VWF levels by VWF:Ac and VWF:RCo, a type 2B VWD subject on replacement had much lower activity estimated by VWF:Ac.Conclusion We conclude that Innovance® VWF Ac is suitable for the diagnosis, classification, and monitoring of VWD, and that it has a number of advantages over VWF:RCo method.
    International journal of laboratory hematology 06/2014; 36(3). · 1.30 Impact Factor
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    ABSTRACT: Background Diagnosis of inherited platelet function disorders (IPFD) is important for appropriate management, and to improve epidemiologic and clinical knowledge. However, there is still a lack of consensus on the diagnostic approach.Objectives To gain knowledge on the current practices for the diagnosis of IPFD worldwide.MethodsA 67 item questionnaire was distributed to the ISTH members and to the members of several hemostasis and thrombosis national societies.ResultsA total of 202 laboratories from 37 countries participated in the survey. The most frequent criterion to define patients with a suspected IPFD was a history of mucocutaneous bleeding and no acquired cause, but heterogeneity on the identification criteria was evident. Only 64.5% of respondents performed a direct clinical interview. On average, each laboratory studied 72 patients/year. The most commonly used laboratory equipments were the light-transmission aggregometer (LTA), the platelet function analyzer-100 (PFA-100®), and flow-cytometer. Screening tests were platelet count, peripheral blood smear, LTA, PFA-100®. Second step tests were flow-cytometry, molecular genetic analysis and electron microscopy. Methodologies used varied widely. In total, around 14,000 patients were investigated yearly and 60% turned out not to have a defect. Of the remaining 40%, only 8.7% received a diagnosis at a molecular level.Conclusions Many laboratories worldwide are involved in the diagnosis of IPFD. A large fraction of the patients studied remain without a diagnosis. A high variability in the diagnostic approaches is evident.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 06/2014; · 6.08 Impact Factor
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    C. P. M. Hayward, K. A. Moffat, L. Graf
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    ABSTRACT: Diagnostic tests for von Willebrand disease (VWD) are important for the assessment of VWD, which is a commonly encountered bleeding disorder worldwide. Technical innovations have been applied to improve the precision and lower limit of detection of von Willebrand factor (VWF) assays, including the ristocetin cofactor activity assay (VWF:RCo) that uses the antibiotic ristocetin to induce plasma VWF binding to glycoprotein (GP) IbIXV on target platelets. VWF-collagen-binding assays, depending on the type of collagen used, can improve the detection of forms of VWD with high molecular weight VWF multimer loss, although the best method is debatable. A number of innovations have been applied to VWF:RCo (which is commonly performed on an aggregometer), including replacing the target platelets with immobilized GPIbα, and quantification by an enzyme-linked immunosorbent assay (ELISA), immunoturbidimetric, or chemiluminescent end-point. Some common polymorphisms in the VWF gene that do not cause bleeding are associated with falsely low VWF activity by ristocetin-dependent methods. To overcome the need for ristocetin, some new VWF activity assays use gain-of-function GPIbα mutants that bind VWF without the need for ristocetin, with an improved precision and lower limit of detection than measuring VWF:RCo by aggregometry. ELISA of VWF binding to mutated GPIbα shows promise as a method to identify gain-of-function defects from type 2B VWD. The performance characteristics of many new VWF activity assays suggest that the detection of VWD, and monitoring of VWD therapy, by clinical laboratories could be improved through adopting newer generation VWF assays.
    International journal of laboratory hematology 06/2014; 36(3). · 1.30 Impact Factor
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    ABSTRACT: We analyzed results from the External quality Control of diagnostic Assays and Tests program to assess current clinical laboratory practice and performance of different methods for factor XIII (FXIII) testing internationally. FXIII proficiency testing data from all eight surveys conducted in 2010 and 2011 were analyzed (1,283 results), comparing the three available methods for detecting FXIII deficiency, thus including clot-solubility qualitative activity, quantitative activity, and antigen. Clot-solubility qualitative assays detected a deficiency in only 16% (11/69) of samples with less than 2% FXIII. Assays using added thrombin detected more deficiencies (33%) than did assays without added thrombin (11%). The most commonly used quantitative activity method tended to produce higher results for low FXIII samples than other quantitative activity methods. Antigen results generally showed good accuracy compared with expected levels. The mean interlaboratory coefficients of variation showed wide variability, especially for samples with less than 10% FXIII activity. Laboratory self-classification of results (as normal vs. abnormal) was good, and was slightly better for specimens with ≤ 25% FXIII than for specimens with 26 to ≥ 70% FXIII. We conclude that quantitative activity assays perform better for detecting FXIII deficiency than clot solubility assays, although some quantitative activity assays overestimate low FXIII levels.
    Seminars in Thrombosis and Hemostasis 02/2014; · 4.22 Impact Factor
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    ABSTRACT: Light transmission aggregometry (LTA) is the most common method used to assess platelet function. However, there is no universal standard for its performance. The Platelet Physiology Subcommittee of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis formed a working party of experts with the aim of producing a series of consensus recommendations for standardizing LTA. Due to a lack of investigations that directly compared different methodologies to perform LTA studies, there were insufficient data to develop evidence-based guidelines. Therefore, the RAND method was used, which obtains a formal consensus among experts about the appropriateness of health care interventions, particularly when scientific evidence is absent, scarce and/or heterogeneous. Using this approach, each expert scored as "appropriate", "uncertain" or "inappropriate" a series of statements about the practice of LTA, which included pre-analytical variables, blood collection, blood processing, methodological details, choice of agonists and the evaluation and reporting of results. After presentation and public discussion at SSC meetings, the assessments were further refined to produce final consensus recommendations. Before delivering the recommendations, a formal literature review was performed using a series of defined search terms about LTA. Of the 1830 potentially relevant studies identified, only 14 publications were considered to be actually relevant for review. Based upon the additional information, 6 consensus statements were slightly modified. The final statements were presented and discussed at the SSC Meeting in Cairo (2010) and formed the basis of a consensus document, which is the subject of the present report. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2013; · 6.08 Impact Factor
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    C P M Hayward
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    ABSTRACT: Hematology laboratories have a vital role in providing diagnostic testing for a wide range of blood disorders. Improvements in hematology laboratory diagnostics are highly dependent on new discoveries on blood disorder pathology, the translation of new knowledge into assays for clinical testing purposes, and research that assesses, compares, and optimizes diagnostic practices. This article reviews the author's experiences with research leading to improved blood disorder diagnosis, including research studies on Quebec platelet disorder and other bleeding disorders, evaluations of practice, and research on the external quality assessment of diagnostic testing for platelet function disorders. The importance of research to advancing diagnostic testing for blood disorders is emphasized.
    International journal of laboratory hematology 03/2013; · 1.30 Impact Factor
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    C P M Hayward, K A Moffat
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    ABSTRACT: Laboratory testing is essential for diagnosing bleeding disorders. The tests and panels that laboratories currently use for bleeding disorder evaluation are not standardized, although most offer coagulation screening tests in bleeding disorder panels. Some tests for bleeding disorders, including von Willebrand factor multimer assays and tests for rarer disorders, are not widely available. Accordingly, clinicians and laboratories need tailored strategies for evaluating common and rare bleeding disorders. Coagulation screening tests have high specificity, however, false positives and false negatives do occur among subjects evaluated for bleeding disorders and more specific tests (e.g., factor assays) are required to further assess abnormalities. Tests for defects in primary hemostasis have similar high specificity but much greater sensitivity for common bleeding disorders than coagulation screening tests. Nonetheless, extensive testing fails to establish a diagnosis in a significant number of individuals considered to have significant bleeding problems. Rare bleeding disorder investigations are important to diagnose some conditions, particularly those with delayed-onset bleeding, such as factor XIII deficiency, α2 antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency, and Quebec platelet disorder. These issues need careful consideration when assessing patients for congenital and acquired bleeding problems.
    International journal of laboratory hematology 03/2013; · 1.30 Impact Factor
  • Natalia Bunimov, Nola Fuller, Catherine P M Hayward
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    ABSTRACT: Genetic investigations have led to important advances in our knowledge of genes, proteins, and microRNA that influence circulating platelet counts, platelet size, and function. The application of genome-wide association studies (GWAS) to platelet traits has identified multiple loci with a significant association to platelet number, size, and function in aggregation and granule secretion assays. Moreover, the genes altered by disease-causing mutations have now been identified for several platelet disorders, including X-linked recessive, autosomal dominant, and autosomal recessive platelet disorders. Some mutations that cause inherited platelet disorders involve genes that GWAS have associated to platelet traits. Although disease-causing mutations in many rare and syndromic causes of platelet disorders have now been characterized, the genetic mutations that cause common inherited platelet disorders, and impair platelet aggregation and granule secretion, are largely unknown. This review summarizes current knowledge on the genetic loci that influence platelet traits, including the genes with well-characterized mutations in certain inherited platelet disorders.
    Seminars in Thrombosis and Hemostasis 03/2013; · 4.22 Impact Factor
  • Catherine P M Hayward, Kathryn E Webert
    Seminars in Thrombosis and Hemostasis 03/2013; 39(2):113-6. · 4.22 Impact Factor
  • Catherine P M Hayward, Karen A Moffat, Yang Liu
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    ABSTRACT: Bleeding disorder panels often include the prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen level, and thrombin time (TT). We explored the detection of abnormalities from bleeding disorders by these tests among subjects referred for bleeding disorder assessments, using data from a bleeding disorder study to determine sensitivities and specificities. Among subjects referred to hematologists for bleeding disorder assessment, coagulation defects were uncommon and the APTT and TT detected many nonsignificant abnormalities. While all test and panel specificities were acceptable (88 to 100%), coagulation screening tests were less sensitive to clinically significant abnormalities (1.0 to 2.1%) than von Willebrand disease (VWD) screens (6.7%), and light transmission platelet aggregometry (LTA) (26%). Accordingly, panels comprising PT/INR, APTT, fibrinogen, and TT had lower sensitivity to bleeding disorders (3.7%) than panels expanded to include VWD screens (8.5%), or VWD screens and LTA (30%). These findings have important implications for bleeding disorder diagnosis.
    Seminars in Thrombosis and Hemostasis 09/2012; 38(7):742-52. · 4.22 Impact Factor
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    ABSTRACT: The quality of platelet aggregation and dense granule deficiency testing is important for diagnosing platelet function disorders. After a successful pilot exercise on diagnosing platelet dense granule deficiency by electron microscopy (EM), the North American Specialized Coagulation Laboratory Association (NASCOLA) has launched regular external quality assurance (EQA) for dense granule EM, as well as for the interpretation of platelet aggregation findings. EQA records were analyzed to assess performance. For EM EQA, between 2009 and 2011, there was excellent performance in distinguishing normal from dense granule-deficient samples and good (>70%) agreement on classifying most electron dense structures in platelets. For aggregation EQA, some normal variants were misclassified and overall case interpretations were more acceptable for rare disorders than for common findings. NASCOLA experiences with these EQAs indicate that there is a need to improve the quality of platelet disorder evaluations. For aggregometry interpretations, deficits in performance could be addressed by translating guideline recommendations into practice.
    Seminars in Thrombosis and Hemostasis 06/2012; 38(6):622-31. · 4.22 Impact Factor
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    ABSTRACT: To determine the performance and frequency of protein C reagents currently used by clinical laboratories, we analyzed North American Specialized Coagulation Laboratory Association (NASCOLA) protein C proficiency testing data from 6 surveys conducted in 2009 and 2010 (2009-1 to 2009-3 and 2010-1 to 2010-3). Interlaboratory coefficients of variation (CV) for commonly used reagents on a survey with normal protein C ranged from 8% to 12% for antigenic assays, from 4% to 7% for chromogenic activity assays, and from 7% to 22% for clot-based activity assays. CVs for commonly used reagents on specimens with abnormal protein C ranged from 15% to 24% for antigenic, 4% to 11% for chromogenic, and 10% to 17% for clot-based assays (averaged across 3 surveys). Some reagents were used by relatively few laboratories and therefore additional study may be needed for those reagents. For all commonly used reagents, biases were usually small and often not statistically significant. All assessed reagents were clinically accurate, and were considered acceptable options for a specialized coagulation laboratory.
    American Journal of Clinical Pathology 06/2012; 137(6):909-15. · 2.88 Impact Factor
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    ABSTRACT: Bleeding disorders commonly result from deficiencies or defects in von Willebrand factor (VWF), platelets, coagulation factors, or fibrinolytic proteins. The primary goal of our study was to assess current North American coagulation laboratory practices for diagnosing bleeding disorders, using an on-line patterns-of-practice survey of diagnostic laboratory members of the North American Specialized Coagulation Laboratory Association. The survey examined laboratory approaches to evaluating bleeding disorders, with specific questions about the tests and test panels offered and compliance to recent guideline recommendations on diagnosing von Willebrand disease (VWD) and platelet function disorders. All laboratories responding to the survey performed a prothrombin time/international normalized ratio, an activated partial thromboplastin time, and coagulation factor assays, and many tested for VWD and platelet disorders. However, few laboratories had test panels that evaluated the more common bleeding disorders and few performed some assays, including VWF multimer assessments and assays for fibrinolytic disorders. Additionally, the cutoffs used by laboratories to diagnose type 1 VWD varied considerably, with only a minority following the National Heart Lung Blood Institute recommendations. In contrast, laboratories that tested for platelet function disorders mostly complied with aggregation testing recommendations, as published in the recent North American guidelines. Our results indicate that there are some gaps in the strategies used by laboratories to diagnose bleeding disorders that might be addressed by development of further guidelines and test algorithms that emphasize evaluations for common bleeding disorders. Laboratories may also benefit from guidelines on test interpretation, and external evaluation of their bleeding disorder testing strategies.
    American Journal of Hematology 01/2012; 87 Suppl 1:S45-50. · 4.00 Impact Factor
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    ABSTRACT: Platelet aggregometry and dense granule adenosine triphosphate (ATP) release assays are helpful to diagnose platelet disorders. Some laboratories simultaneously measure aggregation and ATP release using Chronolume® a commercial reagent containing D-luciferin, firefly luciferase and magnesium. Chronolume® can potentiate sub-maximal aggregation responses, normalising canine platelet disorder findings. We investigated if Chronolume® potentiates human platelet aggregation responses after observing discrepancies suspicious of potentiation. Among patients simultaneously tested by light transmission aggregometry (LTA) on two instruments, 18/43 (42%), including 14/24 (58%) with platelet disorders, showed full secondary aggregation with one or more agonists only in tests with Chronolume®. As subjects with Quebec platelet disorder (QPD) did not show the expected absent secondary aggregation responses to epinephrine in tests with Chronolume®, the reason for the discrepancy was investigated using samples from 10 QPD subjects. Like sub-threshold ADP (0.75 μM), Chronolume® significantly increased QPD LTA responses to epinephrine (p<0.0001) and it increased both initial and secondary aggregation responses, leading to dense granule release. This potentiation was not restricted to QPD and it was mimicked adding 1-2 mM magnesium, but not D-luciferin or firefly luciferase, to LTA assays. Chronolume® potentiated the ADP aggregation responses of QPD subjects with a reduced response. Furthermore, it increased whole blood aggregation responses of healthy control samples to multiple agonists, tested at concentrations used for the diagnosis of platelet disorders (p values <0.05). Laboratories should be aware that measuring ATP release with Chronolume® can potentiate LTA and whole blood aggregation responses, which alters findings for some human platelet disorders, including QPD.
    Thrombosis and Haemostasis 01/2012; 107(4):726-34. · 5.76 Impact Factor
  • Menaka Pai, Karen A Moffat, Elizabeth Plumhoff, Catherine P M Hayward
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    ABSTRACT: Critical values are vital to safe clinical and laboratory practice. To address the lack of information on critical values in coagulation, pattern-of-practice surveys were distributed to members of the North American Specialized Coagulation Laboratory Association. More than 70% of respondents had critical values for commonly performed tests. Median values were as follows: prothrombin time, more than 37 seconds; international normalized ratio, more than 5; activated partial thromboplastin time, more than 100 seconds; and fibrinogen level, less than 100 mg/dL. Critical value reporting generated a significant workload, with up to 15% of these tests yielding critical results. The median time to report critical values was 7 minutes for inpatients. Despite the lack of guidelines surrounding critical values in coagulation, this survey confirms that laboratories have reasonable and uniform practices. It also provides critical value medians and ranges for a wide range of tests. Laboratories without critical values or in the process of reviewing their values may find this survey of their peers useful.
    American Journal of Clinical Pathology 12/2011; 136(6):836-41. · 2.88 Impact Factor
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    ABSTRACT: Light transmission platelet aggregometry (LTA) is important to diagnose bleeding disorders. Experts recommend testing LTA with native (N) rather than platelet count adjusted (A) platelet-rich plasma (PRP), although it is unclear if this provides non-inferior, or superior, detection of bleeding disorders. Our goal was to determine if LTA with NPRP is non-inferior to LTA with APRP for bleeding disorder assessments. A prospective cohort of patients, referred for bleeding disorder testing, and healthy controls, were evaluated by LTA using common agonists, NPRP and APRP (adjusted to 250 x 10⁹ platelets/l). Recruitment continued until 40 controls and 40 patients with definite bleeding disorders were tested. Maximal aggregation (MA) data were assessed for the detection of abnormalities from bleeding disorders (all causes combined to limit bias), using sample-type specific reference intervals. Areas under receiver-operator curves (AUROC) were evaluated using pre-defined criteria (area differences: < 0.15 for non-inferiority, > 0 for superiority). Forty-four controls and 209 patients were evaluated. Chart reviews for 169 patients indicated 67 had bleeding disorders, 28 from inherited platelet secretion defects. Mean MA differences between NPRP and APRP were small for most agonists (ranges, controls: -3.3 to 5.8; patients: -3.0 to 13.7). With both samples, reduced MA with two or more agonists was associated with a bleeding disorder. AUROC differences between NPRP and APRP were small and indicated that NPRP were non-inferior to APRP for detecting bleeding disorders by LTA, whereas APRP met superiority criteria. Our study validates using either NPRP or APRP for LTA assessments of bleeding disorders.
    Thrombosis and Haemostasis 09/2011; 106(4):675-82. · 5.76 Impact Factor
  • Catherine P M Hayward
    Thrombosis and Haemostasis 09/2011; 106(4):567-8. · 5.76 Impact Factor
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    ABSTRACT: Platelet dense granule release assays are recommended for diagnosing platelet function disorders and are commonly performed by Lumi-Aggregometer (Chrono-Log, Havertown, PA) assays of adenosine triphosphate (ATP) release. We conducted a prospective cohort study of people tested for ATP release defects to assess bleeding symptoms. Reduced release, with 1 or more agonists, was more common among patients with bleeding disorders than among healthy control subjects (P < .001). The respective likelihood (odds ratio [95% confidence interval]) of a bleeding disorder or an inherited platelet function disorder were high when release was reduced with 1 or more agonists (17 [6-46]; 128 [30-545]), even if aggregation was normal (12 [4-34]; 105 [20-565]). ATP release had high specificity and moderate sensitivity for inherited platelet function disorders, with most abnormalities detected by the combination of 6 μmol/L epinephrine, 5.0 μg/mL collagen, and 1 μmol/L U46619. Platelet ATP release assays are useful for evaluating common bleeding disorders, regardless of aggregation findings.
    American Journal of Clinical Pathology 09/2011; 136(3):350-8. · 2.88 Impact Factor
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    ABSTRACT: Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment.
    Seminars in Thrombosis and Hemostasis 09/2011; 37(6):713-20. · 4.22 Impact Factor

Publication Stats

3k Citations
626.93 Total Impact Points

Institutions

  • 1991–2014
    • McMaster University
      • • Department of Pathology and Molecular Medicine
      • • Health Sciences Centre
      • • Department of Medicine
      • • Faculty of Health Sciences
      Hamilton, Ontario, Canada
  • 2012
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States
  • 2010
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 2009
    • SickKids
      Toronto, Ontario, Canada
  • 2001
    • Columbia University
      • Department of Medicine
      New York City, New York, United States
  • 1997
    • Universidade Federal de São Paulo
      San Paulo, São Paulo, Brazil