Publications by authors named "Michelle Sholzberg"

74 Publications

Cost-effectiveness of eltrombopag versus intravenous immunoglobulin for the perioperative management of immune thrombocytopenia.

Blood Adv 2021 Nov 15. Epub 2021 Nov 15.

McMaster University, Hamilton, Canada.

Eltrombopag has been shown to be non-inferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50mg daily starting dose, with IVIG 1 or 2g/kg (according to local practice) from a Canadian public healthcare payer's perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n=38; IVIG, n=36) and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using non-parametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian dollars per patient. Compared with IVIG, the probability of eltrombopag being cost-effective was 70% even with zero willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2g/kg), eltrombopag saved $2,714 per patient; whereas with the lower dose of IVIG (1g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated non-inferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.
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http://dx.doi.org/10.1182/bloodadvances.2021005627DOI Listing
November 2021

Invisible bleeds: Lived experiences and barriers to care for men with hemophilia.

J Thromb Haemost 2021 Oct 24. Epub 2021 Oct 24.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Introduction: Guidelines of the World Federation of Hemophilia support the provision of equitable, optimal care for people with hemophilia (PWH). However, limited research exists examining the lived experiences of PWH or the barriers to care they may encounter. The primary objective of this exploratory study was to describe the experiences of men with hemophilia in Canada.

Methods: We conducted a qualitative descriptive study using a semistructured interview guide and analyzed transcribed interviews using inductive thematic content analysis. Inclusion criteria were: age ≥18 years, English-speaking, and confirmed diagnosis of inherited hemophilia A or B.

Results: A total of 11 participants were interviewed. Median age was 39 years old (29-73 years old), and diagnoses included severe hemophilia A (n = 5), mild hemophilia A (n = 2), and severe hemophilia B (n = 4). Three primary themes arose: (1) impact on identity and daily life; (2) dynamic changes in treatment; and (3) barriers to care and identified needs. Major subthemes included chronic pain and activity limitation, psychosocial burden, and symptom normalization. Multidisciplinary care, coordinated surgical care, improved emergency care, and clear care plans were identified as ongoing needs.

Discussion: Men with hemophilia described significant symptom burden and areas of ongoing need. Collaborative efforts between hematologists, emergency room physicians, and surgeons to establish hospital-specific testing, treatment and referral guidelines, and regular hemophilia treatment center audits may help address these care gaps, providing more person-centered, equitable care. Future work is required to implement these strategies and monitor their effects.
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http://dx.doi.org/10.1111/jth.15570DOI Listing
October 2021

The impact of extended half-life factor concentrates on patient reported health outcome measures in persons with hemophilia A and hemophilia B.

Res Pract Thromb Haemost 2021 Oct 11;5(7):e12601. Epub 2021 Oct 11.

British Columbia Hemophilia Treatment Centre - Adult Division Vancouver British Columbia Canada.

Background: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) were the only available extended half-life (EHL) products in Canada during 2016 to 2018.

Objectives: To evaluate if patient-reported outcome measures (PROMs) improved in Canadian persons with hemophilia who switched from standard half-life (SHL) to EHL products (rFVIIIFc/rFIXFc).

Patients/methods: This prospective cohort study enrolled persons with moderate or severe hemophilia aged ≥6 years who switched to rFVIIIFc/rFIXFc (2016-2018) and those who remained on SHL. Health-related quality of life (HRQoL) was assessed using the Haemophilia-specific Quality of Life (Haem-A-QoL) and 36-item Short-Form Survey (SF-36) at baseline, 3-months, 12 months, and 24 months. Other PROMs included the Work Productivity and Impairment Questionnaire, chronic pain scale, partner/parent ratings of mood, International Physical Activity Questionnaire, and Treatment Satisfaction Questionnaire for Medication. We identified meaningful changes using minimally important difference for SF-36 and responder definition for Haem-A-QoL.

Results: We enrolled 25 switchers (16 rFVIIIFc, 9 rFIXFc) and 33 nonswitchers. Those switched to rFVIIIFc/rFIXFc had improved overall HRQoL, and improved subscale physical activity, mental health, and social functioning at 3 months. The rFIXFc switchers had improved chronic pain and ability to engage in normal activities while the rFVIIIFc switchers had improved treatment satisfaction. There was no change in work impairment after the switch. Observed improvement disappeared by 24 months in most domains.

Conclusion: Switching from SHL to rFVIIIFc/rFIXFc resulted in short-term meaningful improvement in overall HRQoL and other PROMs in a small proportion. Longitudinal changes on PROMs are affected by ceiling effects and response shift, warranting further studies in instrument optimization in the era of EHL and nonfactor products.
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http://dx.doi.org/10.1002/rth2.12601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505988PMC
October 2021

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

BMJ 2021 10 14;375:n2400. Epub 2021 Oct 14.

St Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.

Design: Randomised controlled, adaptive, open label clinical trial.

Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.

Participants: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237).

Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.

Main Outcome Measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.

Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69).

Conclusions: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial.

Trial Registration: ClinicalTrials.gov NCT04362085.
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http://dx.doi.org/10.1136/bmj.n2400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515466PMC
October 2021

Commentary: surviving sexism in bleeding disorders affecting women.

Br J Haematol 2021 Oct 7. Epub 2021 Oct 7.

Department of Medicine, Queen's University, Kingston, ON, Canada.

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http://dx.doi.org/10.1111/bjh.17881DOI Listing
October 2021

Suboptimal iron deficiency screening in pregnancy and the impact of socioeconomic status in a high-resource setting.

Blood Adv 2021 11;5(22):4666-4673

Hematology Division, Department of Medicine, University of Toronto, Toronto, Canada.

Iron deficiency (ID) anemia in pregnancy is associated with poor maternal and childhood outcomes, yet ferritin testing, the standard test for ID, is not considered part of routine prenatal bloodwork in Canada. We conducted a retrospective cohort study of 44 552 pregnant patients with prenatal testing at community laboratories in Ontario, Canada, to determine the prevalence of ferritin testing over 5 years. Secondary objectives were to determine the prevalence and severity of ID and to identify clinical and demographic variables that influence the likelihood of ID screening. A total of 59.4% of patients had a ferritin checked during pregnancy; 71.4% were ordered in the first trimester, when the risk of ID is lowest. Excluding patients with abnormally elevated ferritins, 25.2% were iron insufficient (30-44 µg/L) and 52.8% were iron deficient (≤29 µg/L) at least once in pregnancy. A total of 8.3% were anemic (hemoglobin <105 g/L). The proportion of anemic patients with a subsequent ferritin test in pregnancy ranged from 22% to 67% in the lowest and highest anemia severity categories, respectively. Lower annual household income was negatively associated with the odds of a ferritin test; compared with those in the fifth (ie, highest) income quintile, the odds of ferritin testing for patients in the first, second, and fourth quintiles were 0.83 (95% confidence interval [CI], 0.74-0.91), 0.82 (95% CI, 0.74-0.91), and 0.86 (95% CI, 0.77-0.97), respectively. These data highlight gaps in prenatal care and issues of health equity that warrant harmonization of obstetrical guidelines to recommend routine ferritin testing in pregnancy.
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http://dx.doi.org/10.1182/bloodadvances.2021004352DOI Listing
November 2021

Safety of idarucizumab in the reversal of dabigatran at six tertiary care Ontario hospitals.

Res Pract Thromb Haemost 2021 Jul 7;5(5):e12535. Epub 2021 Aug 7.

Departments of Laboratory Medicine and Pathobiology & Department of Medicine University of Toronto Toronto ON Canada.

Background: Idarucizumab, a monoclonal antibody fragment that reverses the anticoagulant effect of dabigatran, was approved for use in Canada in 2016.

Objective: Our objective was to assess the safety of idarucizumab among patients who received the drug within the first 3 years of its use in Canada.

Patients/methods: We performed a retrospective health records review of all idarucizumab use, excluding use in those <18 years of age, between May 16, 2016, and August 1, 2019, at six Ontario tertiary care hospitals. The primary outcome was mortality. The secondary outcomes were in-hospital arterial thrombotic event (ATE), in-hospital venous thromboembolism (VTE), length of hospital stay, and length of critical care stay.

Results: A total of 85 patients received idarucizumab during the study period for the following indications: 37 (43.5%) for spontaneous bleeding, 28 (32.9%) for traumatic bleeding, 11 (12.9%) for emergency surgeries/procedures, 5 (5.9%) for elective surgeries/procedures, and 4 (4.7%) for other indications. Nineteen patients (22.4%; 95% confidence interval [CI], 14.8%-32.3%) did not survive their hospitalization. During hospitalization, two patients (2.4%; 95% CI, 0.7%-8.2%) had ATE, and three patients (3.5%; 95% CI, 1.2%-9.9%) had VTE. The median length of stay was 8 (interquartile range [IQR], 2.5-13) days in hospital and 3 (IQR, 2-5) days in critical care.

Conclusions: Compared with clinical trial data, we found a numerically higher rate of mortality and similar rate of ATE and VTE among patients treated with idarucizumab in the real world.
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http://dx.doi.org/10.1002/rth2.12535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348998PMC
July 2021

Tranexamic acid evidence and controversies: An illustrated review.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12546. Epub 2021 Jul 14.

Department of Medicine St. Michael's Hospital University of Toronto Toronto ON Canada.

Tranexamic acid (TXA) is an antifibrinolytic agent commonly used for the treatment or prevention of bleeding. Indications for TXA are diverse, including heavy menstrual bleeding, trauma, postpartum hemorrhage, traumatic brain injury, and surgical site bleeding. Despite decades of use and a robust body of evidence, hesitancy using TXA persists in many clinical settings. This illustrated review describes the history, pharmacology, and practical considerations of TXA use. We also describe the major landmark randomized controlled trials of TXA and their implications. Finally, we review the evidence around common controversies surrounding TXA such as the risk of thrombosis, prescription along with combined hormonal contraceptives, and use in patients with gross hematuria.
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http://dx.doi.org/10.1002/rth2.12546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279901PMC
July 2021

Heparin for Moderately Ill Patients with Covid-19.

medRxiv 2021 Jul 12. Epub 2021 Jul 12.

Background: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.

Methods: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.

Results: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).

Conclusions: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.
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http://dx.doi.org/10.1101/2021.07.08.21259351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282099PMC
July 2021

Real-World Data on the Effectiveness and Safety of wilate for the Treatment of von Willebrand Disease.

TH Open 2021 Jul 4;5(3):e264-e272. Epub 2021 Jul 4.

Werlhof-Institut GmbH, Hannover, Germany.

 The efficacy and safety of wilate (human von Willebrand factor/coagulation factor VIII) in patients with von Willebrand disease (VWD) has been demonstrated in clinical trials. Here, we present real-world data on the use of wilate for the routine care of patients with VWD.  The objectives of this observational, prospective, phase 4 study were to evaluate the safety, tolerability, and effectiveness of wilate in on-demand treatment of bleeding episodes (BEs), long-term prophylaxis, and surgical prophylaxis among patients with any type of VWD.  Patients were enrolled at 31 study centers in 11 countries and followed for up to 2 years. Safety endpoints included adverse drug reactions (ADRs) and drug tolerability. Effectiveness was assessed using annualized bleeding rates (ABRs) during prophylaxis and predefined criteria for the treatment of BEs and surgical prophylaxis.  A total of 111 patients (76 [68%] female) including 41 (37%) children were treated with wilate. Twenty-five patients received prophylaxis, 29 on-demand treatment, and 62 surgical prophylaxis. Tolerability was rated by patients as "excellent" for 96.2% of 6,497 infusions. No unexpected ADRs or thrombotic events were reported. Median ABR during prophylaxis was 1.9. Effectiveness was assessed as "excellent" or "good" by patients and investigators for 100% of BEs treated on-demand, 98% (patient rating) and 99% (investigator rating) of breakthrough BEs, and 99% of surgical procedures (investigator rating).  wilate was safe, well tolerated, and effective for the prevention and treatment of bleeding in pediatric and adult VWD patients in a real-world setting.
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http://dx.doi.org/10.1055/s-0041-1730283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255103PMC
July 2021

Reconnaître, traiter et signaler les cas de thrombocytopénie immunitaire thrombotique induite par un vaccin.

CMAJ 2021 Jul;193(26):E1031-E1033

Départements de médecine, de médecine de laboratoire et de pathobiologie (Sholzberg), Hôpital St. Michael's, Université de Toronto; Département de médecine (Arnold), Université McMaster, Toronto, Ont.; rédacteur adjoint principal (Laupacis), CMAJ, Ottawa, Ont.

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http://dx.doi.org/10.1503/cmaj.210882-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248567PMC
July 2021

Factor product utilization and health outcomes in patients with haemophilia A and B on extended half-life concentrates: A Canadian observational study of real-world outcomes.

Haemophilia 2021 Sep 23;27(5):751-759. Epub 2021 Jun 23.

British Columbia Hemophilia Treatment Centre - Adult Division, Vancouver, British Columbia, Canada.

Introduction: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) became available in Canada in 2016 and were the only extended half-life (EHL) factor concentrates available in Canada until 2018.

Objectives: We aim to describe the change in product utilization in Canadians who switched to rFVIIIFc/rFIXFc.

Methods: This prospective and retrospective cohort study enrolled males aged ≥6 years with moderate or severe haemophilia who switched to rFVIIIFc/rFIXFc and those who remained on standard half-life (SHL) between 2016 and 2018. Factor utilization and annualized bleeding rates (ABR) were collected at baseline, 1-year and 2-years. Due to low prospective enrolment (n = 25 switchers), prospective and retrospective data were pooled.

Results: 125 switchers (93 rFVIIIFc, 32 rFIXFc) and 33 non-switchers were included. The median age was 17 (rFVIIIFc) and 38 years (rFIXFc). Prior to switch, over 80% were on prophylaxis. There was a statistically significant reduction in the prescribed weekly prophylactic dose after the switch to rFVIIIFc/rFIXFc for all age groups, with a corresponding reduction (15-16%) in actual annualized FIX utilization in switchers (combined adults and children) to rFIXFc, and a smaller non-significant reduction in actual annualized FVIIII utilization (7%) in children who switched to rFVIIIFc. A significant reduction in the median ABR was only observed in children who switched to rFVIIIFc, but not in adults who switched to rFVIIIFc or rFIXFc.

Conclusion: Switching from SHL to EHL products led to a small reduction in factor utilization, while preserving a low ABR in children and adults with haemophilia. Further patient-reported outcomes data will further elucidate the role of EHL in the haemophilia landscape.
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http://dx.doi.org/10.1111/hae.14369DOI Listing
September 2021

Recognizing, managing and reporting vaccine-induced immune thrombotic thrombocytopenia.

CMAJ 2021 Jun 14;193(24):E913-E915. Epub 2021 May 14.

Departments of Medicine, and Laboratory Medicine and Pathobiology (Sholzberg), St. Michael's Hospital, University of Toronto; Department of Medicine (Arnold), McMaster University, Toronto, Ont.; Senior Deputy Editor (Laupacis), CMAJ, Ottawa, Ont.

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http://dx.doi.org/10.1503/cmaj.210882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248452PMC
June 2021

Evaluating hemostatic thresholds for neuraxial anesthesia in adults with hemorrhagic disorders and tendencies: A scoping review.

Res Pract Thromb Haemost 2021 May 4;5(4):e12491. Epub 2021 May 4.

Division of Hematology Department of Medicine and Department of Laboratory Medicine and Pathobiology St. Michael's Hospital Toronto ON Canada.

Neuraxial anesthesia can be complicated by spinal or epidural hematoma and may result in permanent neurologic injury. There is a paucity of literature characterizing this serious complication in patients with congenital and acquired hemorrhagic disorders or tendencies. The objective of this scoping review was to describe the hemostatic laboratory parameters where neuraxial anesthesia has been administered with and without spinal and epidural hematoma in patients with preexisting hemorrhagic disorders and tendencies, including immune thrombocytopenia, gestational thrombocytopenia, thrombocytopenia associated with hypertensive disorders of pregnancy, platelet function disorders, von Willebrand disease, coagulation factor deficiencies, and fibrinogen disorders. A systematic search of Ovid MEDLINE, CINAHL, Embase, Scopus, and Web of Science was performed. Two authors independently reviewed all titles, abstracts, and full texts to determine study eligibility and extract data. Qualitative synthesis of 91 studies revealed significant gaps in our understanding of the risk of spinal and epidural hematoma in patients with hemorrhagic disorders and tendencies, including few studies of males and in nonobstetric settings. Most reviewed articles were small, retrospective studies at high risk for potential bias. With such low-quality data, we were unable to provide any true estimates of the risk of spinal or epidural hematoma for these patients, nor could we attribute any specific hemostatic or laboratory values to increased risk of hematoma. There is a need both for larger and more rigorously designed and reported studies on this subject and for structured, comprehensive recommendations for safe administration and removal of neuraxial anesthesia in patients with hemorrhagic disorders and tendencies.
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http://dx.doi.org/10.1002/rth2.12491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105160PMC
May 2021

Observational study of efficacy and safety of human cell line-derived recombinant factor VIII in Canadian adults with moderately severe and severe haemophilia A.

Haemophilia 2021 May 18;27(3):e419-e421. Epub 2021 Apr 18.

St. Michael's Hospital, and University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1111/hae.14310DOI Listing
May 2021

The problem with population data for the determination of ferritin lower reference interval limits.

Clin Biochem 2021 Jun 26;92:86. Epub 2021 Mar 26.

St Michael's Hospital and University of Toronto Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.clinbiochem.2021.03.013DOI Listing
June 2021

"They don't really take my bleeds seriously": Barriers to care for women with inherited bleeding disorders.

J Thromb Haemost 2021 06 18;19(6):1506-1514. Epub 2021 Apr 18.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.

Introduction: Women with inherited bleeding disorders experience excessive bleeding that may impair their quality of life, making early diagnosis and treatment critical. However, the experiences of these women regarding access to care has been minimally described. The primary objective of this study was to evaluate and describe barriers to care for women with bleeding disorders. This study was a continuation of our previous work describing the lived experiences of these women.

Methods: We undertook a qualitative descriptive study. Inclusion criteria for study enrollment were the following: age ≥18 years, English-speaking, and confirmed diagnosis of an inherited bleeding disorder. Women were recruited across Canada by treating health-care providers and members of the Canadian Hemophilia Society. Telephone interviews were conducted using a semi-structured interview style, transcribed verbatim, and analyzed using descriptive thematic analysis.

Results: A total of 15 participants were interviewed. Median age was 31 years (range 24-70 years). Four primary themes surrounding barriers to care emerged: (1) lack of health-care provider awareness of bleeding disorders, (2) health-care provider dismissal of symptoms, (3) limited access to specialized care and treatment plans, and (4) need for self-education and advocacy.

Discussion: We found that women with inherited bleeding disorders experience tension with the health-care system, feeling unheard and poorly understood. Based on our findings, we identified key knowledge and care gaps that could be addressed with awareness and educational initiatives: patient education on vaginal blood loss, updated medical curricula, clear referral guidelines, and telehealth initiatives for patients residing far from hemophilia treatment centers.
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http://dx.doi.org/10.1111/jth.15311DOI Listing
June 2021

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04 16;77(15):1903-1921. Epub 2021 Mar 16.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA. Electronic address:

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.
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http://dx.doi.org/10.1016/j.jacc.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001PMC
April 2021

Extended half-life factor VIII concentrates in adults with hemophilia A: Comparative pharmacokinetics of two products.

Res Pract Thromb Haemost 2021 Feb 23;5(2):349-355. Epub 2021 Feb 23.

Department of Health Research Methods, Evidence, and Impact McMaster University Toronto ON Canada.

Background: The use of pharmacokinetic (PK) studies to help design personalized prophylaxis regimens for factor VIII (FVIII) concentrate in individuals with hemophilia A has been recognized for many years but only became practical for routine clinical use with the availability of web-accessible population PK applications based on Bayesian analysis.

Objective: To compare PK variables using population PK studies done on 2 extended half-life recombinant FVIII concentrates in 23 individuals with hemophilia A after switching from one product to the other.

Methods: We retrospectively analyzed PK parameters derived from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-HEMO) application on 23 individuals with severe or moderately severe hemophilia A who were required to switch from recombinant FVIII Fc (Eloctate; Biogen, Cambridge, MA, USA) to recombinant antihemophilic factor PEGylated (Adynovate; Takeda Pharmaceutical Company, Osaka, Japan) between 2016 and 2017.

Results: There were minor PK differences between Eloctate and Adynovate, but some parameters did reach statistical significance, namely in vivo recovery (mean, 2.73 IU/dL per IU/kg vs 2.41 IU/dL per IU/kg), clearance (mean, 0.163 mL/h vs 0.194 mL/h), and volume of distribution at steady state (mean, 42.5 ml/kg vs 49.8 mL/kg). Smaller nonsignificant trends toward higher values for Adynovate were seen in terminal half-life, area under the curve, and predicted times to 5% and 1% residual FVIII after infusion.

Conclusion: Population PK analysis revealed differences between the two extended half-life FVIII concentrates, reaching significance for in vivo recovery, clearance, and volume of distribution.
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http://dx.doi.org/10.1002/rth2.12476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938611PMC
February 2021

Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial.

Trials 2021 Mar 10;22(1):202. Epub 2021 Mar 10.

St. Michael's Hospital, Applied Health Research Centre, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.

Objectives: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days.

Trial Design: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 10/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients.

Intervention And Comparator: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care.

Main Outcomes: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers.

Randomisation: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment.

Blinding (masking): No blinding involved. This is an open-label trial.

Numbers To Be Randomised (sample Size): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05.

Trial Status: Protocol Version Number 1.4. Recruitment began on May 11, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing.

Trial Registration: ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943934PMC
March 2021

Describing the point prevalence and characteristics of venous thromboembolism in patients with thrombotic thrombocytopenic purpura.

J Thromb Haemost 2020 11 27;18(11):2870-2877. Epub 2020 Aug 27.

Division of Hematology, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada.

Background: Arterial thromboembolic events are relatively common and well-described in patients with thrombotic thrombocytopenic purpura (TTP). However, the literature describing venous thromboembolism (VTE) in TTP is scarce.

Methods: Single-institution retrospective chart review was conducted in TTP patients over a 10-year period to describe the point prevalence of VTE. Data were analyzed using descriptive statistics.

Results: We identified 77 consecutive patients with 123 episodes of TTP. Of these patients, 14 (18%) experienced 16 VTEs (6 pulmonary embolisms, 6 deep vein thromboses, 4 superficial vein thromboses [SVT]). Excluding SVT, the point prevalence of VTE was 14%. All were acute and associated with admission for acute TTP. All patients were treated with plasma exchange (PLEX); 6/8 patients on concurrent PLEX at VTE diagnosis were exchanged with solvent-detergent plasma (SDP). Platelet and lactate dehydrogenase levels at time of VTE diagnosis had largely normalized from presentation values (median 175 × 10 U/L [interquartile range 130.75, 250] and 232 U/L [interquartile range 178.75, 263.5], respectively). Most VTEs (9/16) occurred while patients were not on pharmacologic thromboprophylaxis. All but one VTE was treated with anticoagulation. No VTEs were fatal or massive.

Conclusions: Our data provide additional evidence that TTP patients may be at risk for VTE. It is possible that SDP exerted a prothrombotic effect. TTP-associated VTEs may be pathophysiologically distinct from arterial thromboses because they occur following hematological recovery. VTE thromboprophylaxis was not commonly used. Our findings suggest the need to implement VTE thromboprophylaxis earlier in hospitalized patients with TTP.
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http://dx.doi.org/10.1111/jth.15027DOI Listing
November 2020

Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia.

Br J Haematol 2020 09 23;190(6):933-938. Epub 2020 Jul 23.

Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.

Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy (after ≥2 prior lines of therapy including a second-line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second-line and 54/113 (48%) third-or-later-line patients. Bleeding events were less frequent in second-line (28%) versus third-or-later-line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second-line than third-or-later-line therapy for ITP.
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http://dx.doi.org/10.1111/bjh.16959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540289PMC
September 2020

Emergency Management of Hemophilia.

J Emerg Med 2020 10;59(4):607-608

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.jemermed.2020.04.063DOI Listing
October 2020

Revising Ferritin Lower Limits: It's Time to Raise the Bar on Iron Deficiency.

J Appl Lab Med 2021 04;6(3):765-773

St. Michael's Hospital and University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada.

Ferritin is a key diagnostic marker of iron deficiency (ID), but the interpretative guidance provided to physicians varies significantly. Clear discrepancies exist between clinical guidelines that recommend evidence-based ferritin cutoffs and clinical laboratories that report highly variable ferritin reference intervals (RIs) derived from apparently healthy populations. In this study, clinical laboratories across North America were surveyed to assess the RIs provided with ferritin results. Although clinical guidelines often recommend ferritin cutoffs of 15 or 30 µg/L to identify uncomplicated ID, the survey showed that 18 of 23 responding laboratories reported female RI lower limits well below 15 µg/L. To understand the clinical impact, we analyzed 52 027 unique patient ferritin values over a 5-year period (2013-2017) from a tertiary care hospital. In this population, the 90th percentile ferritin cutoff to identify ID anemia in adults was 24 µg/L in female patients and 25 µg/L in male patients. Distribution of ferritin results in female patients showed that menopausal status had a significant effect on median values, which increased 2- to 3-fold in the postmenopausal state. Furthermore, sorting the data for female patients by physician specialty showed the highest prevalence of low ferritin values in patients seen in obstetrics and gynecology. This study highlights the discrepancy between clinical guidelines and clinical laboratory practice for ferritin reporting and indicates that ferritin RIs, particularly for female patients, are set to an inappropriately low threshold in most clinical laboratories in North America; this level provides good specificity but poor sensitivity when screening for ID.
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http://dx.doi.org/10.1093/jalm/jfaa152DOI Listing
April 2021

Coagulopathie associée à la COVID-19.

CMAJ 2020 11;192(45):E1424

Hôpital St. Michael (Lee) et Département de médecine, Université de Toronto; Réseau de santé Sinaï et Département de médecine (Fralick), Université de Toronto; Hôpital St. Michael et Département de médecine, et de médecine de laboratoire et pathobiologie (Sholzberg), Institut du savoir Li Ka Shing, Université de Toronto, Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.200685-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669293PMC
November 2020

"Everything was blood when it comes to me": Understanding the lived experiences of women with inherited bleeding disorders.

J Thromb Haemost 2020 12 21;18(12):3211-3221. Epub 2020 Oct 21.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.

Introduction: Despite the many symptoms that women with inherited bleeding disorders experience, no study has specifically sought to explore and understand the lived experiences of these women, nor the barriers to care that they may encounter. The primary objective of this study was to describe the lived experiences of women with inherited bleeding disorders.

Methods: Inclusion criteria for study enrollment were the following: age ≥18 years, English speaking, and confirmed diagnosis of an inherited bleeding disorder. Women were recruited across Canada through identification by treating health-care providers and study members of the Canadian Hemophilia Society. Telephone interviews were conducted using a semi-structured interview style, transcribed verbatim, and analyzed using descriptive thematic analysis.

Results: A total of 15 participants were interviewed. Median age was 31 years (24-70 years old). Four primary themes emerged: uncertainties surrounding diagnosis, conceptualization of experience through family bleeding, intensity of bleeding symptoms, and impact of bleeding on identity and daily life.

Discussion: To our knowledge, this is the first study to thoroughly describe the experiences of adult women living with inherited bleeding disorders. We found that these women experience multiple uncertainties around their diagnosis. They conceptualize their bleeding by examining family histories; experience severe symptoms irrespective of their underlying diagnosis; and create identities around their bleeding symptoms, which influence multiple aspects of their life. Next study steps will involve sharing work specifically focused on treatment plans, barriers to care, and factors affecting care access.
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http://dx.doi.org/10.1111/jth.15102DOI Listing
December 2020

COVID-19 and Hypercoagulability.

Clin Adv Hematol Oncol 2020 07;18(7):386-389

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.

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July 2020

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration.

J Thromb Haemost 2020 11 1;18(11):2958-2967. Epub 2020 Oct 1.

Feinstein Institutes for Medical Research and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA.

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed.

Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate.

Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials.

Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.
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http://dx.doi.org/10.1111/jth.15094DOI Listing
November 2020

Hemorrhagic, thrombotic and obstetric complications of congenital dysfibrinogenemia in a previously asymptomatic woman.

Thromb Res 2020 12 19;196:127-129. Epub 2020 Aug 19.

St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.08.028DOI Listing
December 2020

Desmopressin responsiveness by age in type 1 von Willebrand disease.

Res Pract Thromb Haemost 2020 Aug 30;4(6):1046-1052. Epub 2020 May 30.

Department of Medicine University of Toronto Toronto ON Canada.

Background: Patients with type 1 von Willebrand disease (VWD) undergo a desmopressin (DDAVP) responsiveness challenge at diagnosis to assess whether DDAVP reverses their coagulation deficits. Current practice assumes DDAVP responsiveness remains constant over the lifetime. In patients with type 1 VWD, VWF-related parameters increase with age. This study explores whether DDAVP responsiveness also differs with age in this population.

Methods: We conducted a retrospective chart review of 106 patients enrolled at our center since 1990. Our primary outcome was DDAVP responsiveness at 1 hour after DDAVP challenge. Locally weighted scatterplot smoothing fit and Spearman correlation coefficients were used to study the relationship between age and DDAVP responsiveness. For female participants, we used the Kruskal-Wallis test to compare absolute and relative changes in DDAVP responsiveness at various ages.

Results: We had 79 patients (56 female) with type 1 VWD with at least 1 DDAVP challenge. In women with type 1 VWD, the absolute change in DDAVP responsiveness did not vary significantly with age (VWF:antigen [Ag], -0.08,  = .56; VWF:ristocetin cofactor [RCo], -0.16,  = .26; low-molecular-weight component of factor VIII [FVIII:C], -0.01,  = .93), nor did the relative change in DDAVP responsiveness (VWF:Ag, -0.03,  = .86; VWF:RCo, -0.25,  = .09; FVIII:C, -0.14,  = .34). The data plot suggested a relationship.

Conclusion: In women with type 1 VWD, DDAVP responsiveness may vary over the life cycle. Our exploratory findings are limited by our retrospective data, cross-sectional design, and small sample. Future studies should investigate the relationship between age and DDAVP responsiveness prospectively to evaluate whether there is clinical utility in rechallenging postpubertal female patients with type 1 VWD.
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http://dx.doi.org/10.1002/rth2.12354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443436PMC
August 2020
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