Publications by authors named "Donald M Arnold"

152 Publications

Platelet-activating immune complexes identified in critically ill COVID-19 patients suspected of heparin-induced thrombocytopenia.

J Thromb Haemost 2021 Feb 27. Epub 2021 Feb 27.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.

Background: Thrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID-19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID-19 patients may be suspected of heparin-induced thrombocytopenia (HIT), given similar clinical features.

Objectives: We investigated the presence of platelet-activating anti-platelet-factor 4 (PF4)/heparin antibodies in critically ill COVID-19 patients suspected of HIT.

Patients/methods: We tested 10 critically ill COVID-19 patients suspected of HIT for anti-PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti-human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS-CoV-2 antibodies were measured using an in-house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin-13 Domain (ADAMTS13) activity and the presence of anti-ADAMTS13 antibodies.

Results: Heparin-induced thrombocytopenia was excluded in all samples based on anti-PF4/heparin antibody and SRA results. Notably, six COVID-19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)-mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID-19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy.

Conclusions: Our study identifies platelet-activating ICs as a novel mechanism that contributes to critically ill COVID-19.
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http://dx.doi.org/10.1111/jth.15283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014456PMC
February 2021

Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination.

Am J Hematol 2021 Feb 19. Epub 2021 Feb 19.

Division of Pediatric Hematology/Oncology, New York Presbyterian Hospital - Weill Cornell, New York, New York.

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http://dx.doi.org/10.1002/ajh.26132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014568PMC
February 2021

A comparative study of platelet factor 4-enhanced platelet activation assays for the diagnosis of heparin-induced thrombocytopenia.

J Thromb Haemost 2021 Apr 19;19(4):1096-1102. Epub 2021 Feb 19.

Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada.

Background: Functional platelet activation assays, such as the serotonin release assay (SRA), are the gold standard for the diagnosis of heparin-induced thrombocytopenia (HIT). Recently, platelet activation assays using added platelet factor 4 (PF4) have been described and suggest improved sensitivity. Direct comparisons of these assays have not been performed.

Objective: We compare the performance characteristics of three PF4-enhanced platelet activation assays, the PF4/heparin-SRA (PF4/hep-SRA), the PF4-SRA, and the P-selectin expression assay (PEA), at a single reference laboratory.

Methods: Serum samples from two cohorts of patients were used. The referral cohort (n = 84) included samples that had previously undergone routine diagnostic testing for HIT and tested positive or negative using the SRA. The clinical cohort (n = 101) consisted of samples from patients with clinically confirmed HIT whose serum contained platelet-activating antibodies. We simultaneously tested all samples in PF4-enhanced SRA-based assays (PF4/hep-SRA, PF4-SRA) and the flow cytometry-based PEA.

Results: In the referral cohort, the three PF4-enhanced assays identified all samples that were previously determined to be positive in the SRA. However, specificity of the PF4/hep-SRA was 96.6%, the PF4-SRA was 84.7%, and the PEA was 67.8%. In the clinical cohort of samples, all SRA-based assays displayed high performance characteristics (>92.1% sensitivity, >98.4% specificity). Sensitivity and specificity of the PEA was the lowest, 65.8% and 63.5%, respectively; but improved to 92.1% and 96.8% using preselected platelet donors.

Conclusions: All PF4-enhanced assays demonstrated good performance characteristics when platelet donors were preselected. Further comparisons across multiple laboratories should be conducted for consensus on optimal HIT diagnostic testing.
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http://dx.doi.org/10.1111/jth.15233DOI Listing
April 2021

Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT?

Am J Hematol 2021 03 29;96(3):320-329. Epub 2020 Dec 29.

Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada.

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.
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http://dx.doi.org/10.1002/ajh.26075DOI Listing
March 2021

Immune thrombocytopenia (ITP) World Impact Survey (iWISh): Patient and physician perceptions of diagnosis, signs and symptoms, and treatment.

Am J Hematol 2021 02 19;96(2):188-198. Epub 2020 Dec 19.

Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York, USA.

Immune thrombocytopenia (ITP) is now well-known to reduce patients' health-related quality of life. However, data describing which signs and symptoms patients and physicians perceive as having the greatest impact are limited, as is understanding the full effects of ITP treatments. I-WISh (ITP World Impact Survey) was an exploratory, cross-sectional survey designed to establish the multifaceted impact of ITP, and its treatments, on patients' lives. It focused on perceptions of 1507 patients and 472 physicians from 13 countries regarding diagnostic pathway, frequency and severity of signs and symptoms, and treatment use. Twenty-two percent of patients experienced delayed diagnosis (caused by several factors), 73% of whom felt anxious as a result. Patients rated fatigue among the most frequent, severe symptom associated with ITP at diagnosis (58% most frequent; 73% most severe), although physicians assigned it lower priority (30%). Fatigue was one of the few symptoms persisting at survey completion (50% and 65%, respectively) and was the top symptom patients wanted resolved (46%). Participating physicians were experienced at treating ITP, thereby recognizing the need to limit corticosteroid use to newly-diagnosed or first-relapse patients and espoused increased use of thrombopoietin receptor agonists and anti-CD20 after relapse in patients with persistent/chronic disease. Patient and physicians were largely aligned on diagnosis, symptoms, and treatment use. I-WISh demonstrated that patients and physicians largely align on overall ITP symptom burden, with certain differences, for example, fatigue. Understanding the emotional and clinical toll of ITP on the patient will facilitate shared decision-management, setting and establishment of treatment goals and disease stage-appropriate treatment selection.
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http://dx.doi.org/10.1002/ajh.26045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898610PMC
February 2021

Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): Impact of ITP on health-related quality of life.

Am J Hematol 2021 02 19;96(2):199-207. Epub 2020 Dec 19.

Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York, USA.

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health-related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. The ITP World Impact Survey (I-WISh) was a cross-sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP-related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well-being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty-six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. Note, I-WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi-dimensional impact of ITP on patients' lives as an integral component of disease management.
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http://dx.doi.org/10.1002/ajh.26036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898815PMC
February 2021

International survey on Helicobacter pylori testing in patients with immune thrombocytopenia: Communication of the platelet immunology scientific and standardization committee.

J Thromb Haemost 2021 01;19(1):287-296

Division of Hematology and Thromboembolism, Department of Medicine, McMaster Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada.

Essentials When to test and treat H pylori among patients with ITP is controversial. We report the results of an international survey administered to physicians with experience treating ITP across 39 countries. The decision to test for H pylori was influenced by country, country of origin, and concomitant gastrointestinal symptoms. Testing and treating for H pylori among patients with ITP varied across geographic regions. ABSTRACT: Background Investigations for patients suspected of immune thrombocytopenia (ITP) lack standardization. A controversial issue is whether such patients should be tested for Helicobacter pylori, a known cause of secondary ITP. Objectives This Scientific and Standardization Committee Communication reports the results of an international survey to describe patterns of practice with respect to screening and treatment of H pylori among patients with ITP. Patients/Methods A 17-item scenario-based questionnaire was delivered to hematologists in countries across the world. The questionnaire was pilot tested before use. We used snowball sampling and a contact list of physicians from the Platelet Disorders Support Association to identify survey respondents. Data were analyzed descriptively. Results A total of 186 respondents from 39 countries completed the survey. Response rate from the snowball sample was 53.6%. Twenty-nine percent (n = 55) of respondents always tested ITP patients for H pylori, and 53% (n = 98) sometimes tested. Of the 37 respondents from Asia and the Middle East, 51.4% (n = 19) always tested for H pylori for the stated reasons of high local prevalence and perceived benefit of treatment on platelet count levels. Respondents were more likely to test patients who were from Asia (145/177, 80%) and who had concomitant gastrointestinal symptoms (133/183, 72%). For eradication therapy, 71 of 118 (60.2%) respondents used the combination of a proton pump inhibitor, clarithromycin, and amoxicillin for 14 days. Conclusions This international survey showed that testing for H pylori was most common in Asia and in patients from Asia. Testing and treating practices varied across geographic regions.
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http://dx.doi.org/10.1111/jth.15136DOI Listing
January 2021

Exploring the components of bleeding outcomes in transfusion trials for patients with hematologic malignancy.

Transfusion 2021 Jan 13;61(1):286-293. Epub 2020 Oct 13.

Department of Medicine, McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada.

Clinically significant bleeding in patients with hematologic malignancies is a heterogeneous composite outcome currently defined as World Health Organization (WHO) bleeding Grades 2, 3, and 4. However, the clinical significance of some minor bleeds categorized as WHO Grades 1 and 2 remains controversial. We analyzed the number and frequency of individual signs and symptoms of WHO Grades 1 and 2 bleeds and explored their association with more severe incident bleeds graded as WHO Grades 3 and 4.

Study Design And Methods: We aggregated daily bleeding assessment data from three randomized controlled trials conducted in patients with hematologic malignancies that used bleeding as an outcome. Cox proportional hazard regression analysis was used to identify signs and symptoms categorized as WHO Grades 1 and 2 bleeds that were associated with more severe bleeds (Grades 3 and 4).

Results: We collected data from 315 patients (n = 5476 daily bleeding assessments; 3383 [61.8%] with a bleed documented). A total of 98.3% (3326/3383) were Grade 1 and 2 bleeds and 1.7% (57/3383) were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Hematuria (hazard ratio, 16.1; 95% confidence interval, 4.4-59.2; P < .0001) was associated with incident Grade 3 or 4 bleeds.

Conclusion: In patients with hematologic malignancy, only hematuria (microscopic and/or macroscopic) was associated with more severe incident bleeds. This findings require validation in independent data sets.
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http://dx.doi.org/10.1111/trf.16126DOI Listing
January 2021

Cluster-randomized trials in transfusion medicine.

Transfusion 2020 Nov 24;60(11):2470-2473. Epub 2020 Sep 24.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1111/trf.16090DOI Listing
November 2020

The mega-importance of de novo lipogenesis in platelet production.

Nat Metab 2020 10;2(10):999-1000

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1038/s42255-020-00282-7DOI Listing
October 2020

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial.

Lancet Haematol 2020 Sep;7(9):e640-e648

Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.

Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10 cells per L before major surgery or less than 50 × 10 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10 cells per L before major surgery or 45 × 10 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.

Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.

Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S2352-3026(20)30227-1DOI Listing
September 2020

The role of fluid-phase immune complexes in the pathogenesis of heparin-induced thrombocytopenia.

Thromb Res 2020 10 6;194:135-141. Epub 2020 Jun 6.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada. Electronic address:

Immune complexes assemble on the platelet surface and cause Fc-mediated platelet activation in heparin-induced thrombocytopenia (HIT); however, it is not known if fluid-phase immune complexes contribute to HIT. The objective of this study was to understand the role of fluid-phase immune complexes in platelet activation and HIT. Binding of wild-type and 15 platelet factor 4 (PF4) mutants to platelets was measured using flow cytometry. Platelet activation was measured using the PF4-dependent C-serotonin release assay (PF4-SRA) with KKO and a HIT-patient plasma in the presence of wild-type or PF4 mutants. To activate platelets, we found that a minimal level of wild-type PF4 is required to bind the platelet surface in the presence of KKO (2.67 relative MFI) or HIT-patient plasma (1.71 relative MFI). Only a subset of PF4 mutants was able to support platelet activation, despite having lower surface binding than the minimum binding required of wild-type PF4 (9 mutants with KKO and 2 mutants with HIT-patient plasma). Using individual PF4 mutants, we identified that HIT immune complexes can be formed in fluid-phase and induce platelet activation. Further studies are required to investigate the role of fluid-phase HIT immune complexes in the development of thrombocytopenia and thrombosis associated with clinical HIT.
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http://dx.doi.org/10.1016/j.thromres.2020.06.012DOI Listing
October 2020

Fetal/neonatal alloimmune thrombocytopenia: a systematic review of impact of HLA-DRB3*01:01 on fetal/neonatal outcome.

Blood Adv 2020 07;4(14):3368-3377

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

The most common, severe cases of fetal and neonatal alloimmune thrombocytopenia among whites are caused by antibodies against human platelet antigen 1a (HPA-1a). The aims of this systematic review and meta-analysis are to determine the association between maternal HLA-DRB3*01:01 and: (1) HPA-1a-alloimmunization and (2) neonatal outcome in children born of HPA-1a-immunized women. A systematic literature search identified 4 prospective and 8 retrospective studies. Data were combined across studies to estimate pooled odds ratios (ORs) and the associated 95% confidence intervals (CIs). The population represented by the prospective studies was more than 150 000. In the prospective studies, there were 64 severely thrombocytopenic newborns (platelet count <50 × 109/L) of whom 3 had intracranial hemorrhage. The mothers of all 64 children were HLA-DRB3*01:01+. The number of severely thrombocytopenic children born of HPA-1a-alloimmunized women in the retrospective studies was 214; 205 of whom were born of HLA-DRB3*01:01+ women. For HLA-DRB3*01:01- women, the OR (95% CI) for alloimmunization was 0.05 (0.00-0.60), and for severe neonatal thrombocytopenia 0.08 (0.02-0.37). This meta-analysis demonstrates that the risk of alloimmunization and of having a child with severe thrombocytopenia are both very low for HPA-1a- women who are HLA-DRB3*01:01-.
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http://dx.doi.org/10.1182/bloodadvances.2020002137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391152PMC
July 2020

Platelet autoantibodies in the bone marrow of patients with immune thrombocytopenia.

Blood Adv 2020 07;4(13):2962-2966

Department of Medicine, Michael G. DeGroot School of Medicine and.

Autoantibodies cause platelet destruction in patients with immune thrombocytopenia (ITP); yet only 50% to 60% of patients have detectable platelet autoantibodies in peripheral blood. We hypothesized that in some ITP patients, platelet autoantibodies are sequestered in the bone marrow where pathological immune reactions target megakaryocytes or newly formed platelets. In this study, we modified the platelet glycoprotein-specific assay to test bone marrow aspiration samples for free platelet autoantibodies or antibodies bound to bone marrow cells in aspirate fluid from patients with ITP (n = 18), patients with nonimmune thrombocytopenia (n = 3), and healthy donors (n = 6). We found that 10 (56%) of 18 patients with ITP had autoantibodies in the bone marrow, including 5 (50%) of 10 with autoantibodies in bone marrow only, and 5 (50%) of 10 with autoantibodies in bone marrow and peripheral blood. In comparison, 6 (33%) of 18 ITP patients had autoantibodies in peripheral blood, most of whom (5 [83%] of 6) also had autoantibodies in bone marrow. Bone marrow autoantibodies were not detected in patients with nonimmune thrombocytopenia or healthy donors; however, peripheral blood autoantibodies were detectable in 1 (33%) of 3 patients with nonimmune thrombocytopenia. The sensitivity of platelet autoantibodies for the diagnosis of ITP increased from 60% (peripheral blood testing) to 72% (peripheral blood and bone marrow testing). Immune reactions limited to the bone marrow may be characteristic of certain subsets of ITP patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362381PMC
July 2020

Management of major bleeds in patients with immune thrombocytopenia.

J Thromb Haemost 2020 07 6;18(7):1783-1790. Epub 2020 May 6.

Department of Medicine, McMaster University, Hamilton, ON, Canada.

Background: A standard approach to the recognition and management of major bleeding in immune thrombocytopenia (ITP) is lacking.

Methods: Retrospective cohort study of ITP patients presenting to the emergency department (ED) with severe thrombocytopenia (platelet count <20 × 10 /L) and bleeding in four academic hospitals from 2008 to 2016. We defined a major ITP bleed as a bleed at a critical site or causing hemodynamic instability.

Results: We identified 112 ITP patients (n = 141 visits) who presented to the ED with platelets <20 × 10 /L and bleeding. Twenty--nine patients (26%) had 32 ED visits with major bleeds. Risk factors for major bleeds were older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.06), male sex (OR 3.25, 95% CI 1.22-9.32), and more prior ITP therapies (OR 1.42, 95% CI 1.10-1.87). Acute treatment of major bleeds required a median of three treatments (interquartile range [IQR] 2--4), which included intravenous immune globulin (91% of visits), corticosteroids (78% of visits), and platelet transfusions (75% of visits). Three patients (10%) died, nine (31%) developed recurrent bleeds, one (3%) developed arterial thrombosis, and one (3%) had permanent neurological disability. Six patients presented with minor bleeding and subsequently developed a major bleed after a median of 2 days (IQR 1-3). All six patients had oral purpura and four of six had gross hematuria preceding the major bleed.

Conclusions: Major ITP bleeds are associated with significant morbidity and mortality. Oral purpura and hematuria often preceded major bleeds. Further research is needed to refine the definition of a major ITP bleed and develop evidence-based treatment strategies.
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http://dx.doi.org/10.1111/jth.14809DOI Listing
July 2020

Combination of two complementary automated rapid assays for diagnosis of heparin-induced thrombocytopenia (HIT).

J Thromb Haemost 2020 06 27;18(6):1435-1446. Epub 2020 Apr 27.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.

Background: HIT diagnosis typically uses complementary diagnostic assays (eg, a PF4-dependent enzyme-immunoassay [EIA] and a platelet activation assay such as the serotonin-release assay [SRA]).

Objectives: To determine whether the combination of two automated assays-a latex immunoturbidimetric assay (LIA) that evaluates competitive inhibition of a HIT-like monoclonal antibody and a chemiluminescence immunoassay (CLIA) for detecting anti-PF4/heparin IgG-optimizes diagnostic sensitivity while also yielding good specificity, particularly at high assay reactivities.

Patients/methods: We determined operating characteristics using combined LIA/CLIA results from a HIT observational trial (n = 430; derivation cohort) and 147 consecutive patients with HIT (n = 147; supplementary derivation cohort). We also evaluated 678 consecutive samples referred for HIT testing (replication cohort). LIA/CLIA reactivities were scored individually as "negative" (<1.00 U/mL, 0 points), "weak" (1.00-4.99 U/mL, 1 point), "moderate" (5.00-15.99 U/mL, 2 points) and "strong" (≥16.00 U/mL, 3 points), thus contributing up to 6 points (maximum) when LIA/CLIA results were combined. We also examined whether higher LIA/CLIA scores predicted presence of platelet-activating antibodies by conventional and modified (PF4- or PF4/heparin-enhanced) SRA.

Results: Combined LIA/CLIA testing yielded high diagnostic sensitivity (~99%) similar to EIA. Interpretation of LIA/CLIA results using the 6-point scale indicated progressively greater likelihood for the presence of platelet-activating antibodies with increasing scores (semi-quantitative reactivity). A LIA/CLIA score ≥ 4 points predicted the presence of platelet-activating antibodies by SRA or PF4-enhanced SRA with high probability (~98%).

Conclusion: Combined LIA/CLIA testing optimizes diagnostic sensitivity, with progressively greater probability of detecting platelet-activating antibodies with higher assay reactivity that reaches 98% when both automated assays yield moderate or strong results.
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http://dx.doi.org/10.1111/jth.14794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317897PMC
June 2020

Platelet factor 4 inhibits ADAMTS13 activity and regulates the multimeric distribution of von Willebrand factor.

Br J Haematol 2020 08 4;190(4):594-598. Epub 2020 Mar 4.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

The efficiency of von Willebrand factor (VWF) in thrombus formation is related to its multimeric size, which is controlled by the protease ADAMTS13. However, it is not clear what regulates ADAMTS13 activity. In this study, we investigated whether PF4 could bind to VWF and inhibit ADAMTS13 activity. We found that PF4 binds to VWF and protects against ADAMTS13 activity. We also found that VWF-PF4 complexes circulate in patients with thrombotic thrombocytopenic purpura (TTP). Our data provides the first evidence that PF4 may have a novel role in regulating VWF multimers during primary haemostasis and thrombosis.
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http://dx.doi.org/10.1111/bjh.16553DOI Listing
August 2020

Safety and efficacy of self-administered romiplostim in patients with immune thrombocytopenia: Results of an integrated database of five clinical trials.

Am J Hematol 2020 06 21;95(6):643-651. Epub 2020 Mar 21.

Amgen (Europe) GmbH, Rotkreuz, Switzerland.

Romiplostim self-administration by patients or caregivers may offer time/cost savings to healthcare professionals (HCPs) and convenience for patients who avoid weekly clinic visits. We performed an integrated analysis of five clinical trials to evaluate the efficacy and safety of romiplostim self-administration. Data were analyzed from adults with immune thrombocytopenia (ITP) who received weekly romiplostim via self-administration or from an HCP. Patients who achieved a stable romiplostim dose for ≥3 weeks (HCP group ≥5 weeks to provide an appropriate index date to enable comparisons with the self-administration group) with platelet counts ≥50 × 10 /L were eligible. In the self-administration (n = 621) vs HCP (n = 133) groups, respectively, median age was 53 vs 58 years, median time since primary ITP diagnosis was 3.7 vs 2.5 years, and median baseline platelet count at ITP diagnosis was 19.0 vs 20.0 × 10 /L. In the self-administration and HCP-dosed groups, median romiplostim treatment duration was 89 vs 52 weeks and median total number of doses was 81 vs 50, respectively. In the self-administration and HCP groups, respectively: 95.0% and 100.0% of patients achieved ≥1 platelet response (defined as weekly platelet count ≥50 × 10 /L without rescue medication in previous 4 weeks); the median percentage of weeks with a response was 94.5% and 95.9%; and rescue medication was used in 36.7% and 39.8% of patients. Self-administration did not adversely affect safety; duration-adjusted rates for all treatment-emergent adverse events (TEAEs) and bleeding TEAEs were numerically lower with self-administration. Romiplostim self-administration appears effective and well tolerated in eligible patients with ITP.
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http://dx.doi.org/10.1002/ajh.25776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318268PMC
June 2020

Increased cytotoxic potential of CD8 T cells in immune thrombocytopenia.

Br J Haematol 2020 03 18;188(5):e72-e76. Epub 2019 Dec 18.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.

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http://dx.doi.org/10.1111/bjh.16334DOI Listing
March 2020

American Society of Hematology 2019 guidelines for immune thrombocytopenia.

Blood Adv 2019 12;3(23):3829-3866

Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Background: Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients.

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the management of ITP.

Methods: In 2015, ASH formed a multidisciplinary guideline panel that included 8 adult clinical experts, 5 pediatric clinical experts, 2 methodologists with expertise in ITP, and 2 patient representatives. The panel was balanced to minimize potential bias from conflicts of interest. The panel reviewed the ASH 2011 guideline recommendations and prioritized questions. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence (up to May 2017) and formulate recommendations.

Results: The panel agreed on 21 recommendations covering management of ITP in adults and children with newly diagnosed, persistent, and chronic disease refractory to first-line therapy who have non-life-threatening bleeding. Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists.

Conclusions: There was a lack of evidence to support strong recommendations for various management approaches. In general, strategies that avoided medication side effects were favored. A large focus was placed on shared decision-making, especially with regard to second-line therapy. Future research should apply standard corticosteroid-dosing regimens, report patient-reported outcomes, and include cost-analysis evaluations.
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http://dx.doi.org/10.1182/bloodadvances.2019000966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963252PMC
December 2019

Updated international consensus report on the investigation and management of primary immune thrombocytopenia.

Blood Adv 2019 11;3(22):3780-3817

Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.
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http://dx.doi.org/10.1182/bloodadvances.2019000812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880896PMC
November 2019

Premedication for the prevention of nonhemolytic transfusion reactions: a systematic review and meta-analysis.

Transfusion 2019 12 31;59(12):3609-3616. Epub 2019 Oct 31.

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: The efficacy of premedication for the prevention of nonhemolytic transfusion reactions remains controversial. This systematic review and meta-analysis assessed the effect of premedication on the rate of nonhemolytic transfusion reactions after allogeneic blood transfusion.

Study Design And Methods: We searched the literature using CENTRAL, MEDLINE, EMBASE, ISI Web of Science, and clinicaltrials.gov databases from inception until October 31, 2018. We included all randomized controlled trials comparing premedication to placebo or no treatment in patients receiving any labile blood product. Outcome measures were reported as relative risks (RRs) with 95% confidence intervals (CIs). Data were combined for similar outcomes where appropriate using a random-effects model. Analyses were done at both the patient and transfusion level.

Results: Three randomized trials using acetaminophen and antihistamine as premedication met the inclusion criteria. A total of 517 patients received 4444 red blood cell or platelet transfusions. Pooled patient-level estimates with premedication for all nonhemolytic, febrile nonhemolytic, and minor allergic reactions were RR, 0.92 (95% CI, 0.63-1.35); RR, 0.54 (95% CI, 0.26-1.1); and RR, 1.37 (95% CI 0.81-2.31), respectively. Transfusion-level analyses also showed no benefit with premedication. Of 517 patients randomized, only 27 (5.2%) had a history of transfusion reactions.

Conclusion: Routine premedication with acetaminophen and antihistamines did not prevent nonhemolytic transfusion reactions; however, the estimate of effect was greatest for febrile reactions. The impact of premedication in patients with a prior history of transfusion reactions remains unknown and requires further evaluation in future clinical trials.
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http://dx.doi.org/10.1111/trf.15566DOI Listing
December 2019

Serotonin-release assay-negative heparin-induced thrombocytopenia.

Am J Hematol 2020 01 6;95(1):38-47. Epub 2019 Nov 6.

Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Pathogenic HIT antibodies can be detected by the serotonin-release assay (SRA), a platelet activation test. We have regarded the SRA performed in our medical community ("McMaster" SRA) as having high sensitivity and specificity. Recently, the concept of "SRA-negative HIT" has been proposed for enzyme-immunoassay (EIA)-positive/SRA-negative patients with a HIT-compatible clinical picture, who test positive in a PF4-enhanced platelet activation assay. After identifying an index case of SRA-negative HIT, we estimated the frequency of this condition by performing the "PF4-SRA" (modified SRA using high concentrations of added PF4 rather than heparin) in EIA-positive patients from a cohort study evaluating clinical and laboratory diagnosis of HIT. We defined SRA-negative HIT as patients meeting three criteria: clinical picture compatible with HIT (4Ts ≥ 4 points); EIA-positive (≥1.00 units); and PF4-SRA-positive. Among 430 patients, 35 were EIA-positive/SRA-positive and 27 were EIA-positive/SRA-negative. Among these 27 SRA-negative patients, three were found to have subthreshold levels of platelet-activating antibodies by PF4-SRA, of whom one met clinical criteria for SRA-negative HIT. Thus, based on identifying one patient with SRA-negative HIT within a cohort study that found 35 SRA-positive HIT patients, we estimate the sensitivity of the McMaster SRA for diagnosis of HIT to be 35/36 (97.2%; 95% CI, 85.8-99.9%). Although the McMaster SRA is highly sensitive for HIT, occasional SRA-negative but EIA-positive patients strongly suspected of having HIT can have this diagnosis supported by a PF4-enhanced activation assay such as the PF4-SRA.
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http://dx.doi.org/10.1002/ajh.25660DOI Listing
January 2020

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant.

JAMA Intern Med 2019 Aug 5. Epub 2019 Aug 5.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Importance: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain.

Objective: To investigate the safety of a standardized perioperative DOAC management strategy.

Design, Setting, And Participants: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol.

Interventions: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation.

Main Outcomes And Measures: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure.

Results: The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high-bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high-bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort.

Conclusions And Relevance: In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.
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http://dx.doi.org/10.1001/jamainternmed.2019.2431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686768PMC
August 2019

First-Line Therapy for Immune Thrombocytopenia.

Hamostaseologie 2019 Aug 6;39(3):259-265. Epub 2019 Jun 6.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Immune thrombocytopenia (ITP) is an autoimmune disease affecting blood platelets that causes thrombocytopenia and an increased risk of bleeding. First-line therapy is indicated for patients with bleeding complications or who are at increased risk of bleeding, and the decision to initiate therapy depends not only on the platelet count, but also on other endpoints including quality of life. The choice of first-line therapy depends primarily on how quickly a platelet count response is required, with intravenous immune globulin providing the more rapid response, followed by high-dose dexamethasone and prednisone. In this narrative review, we discuss key issues with first-line therapy in ITP including when to initiate therapy, treatment options and special considerations for children. Evidence-based guidelines are lacking for the emergency management of patients with ITP who present with significant bleeding; we provide our approach to this critical situation.
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http://dx.doi.org/10.1055/s-0039-1684031DOI Listing
August 2019

Sex-mismatched red blood cell transfusions and mortality: A systematic review and meta-analysis.

Vox Sang 2019 Jul 23;114(5):505-516. Epub 2019 May 23.

McMaster Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada.

Background And Objectives: Selection of a compatible red blood cell (RBC) unit does not include matching for donor sex. This systematic review and meta-analysis aims to summarize the evidence examining the impact of sex-mismatched RBC transfusion on recipient mortality.

Materials And Methods: Ovid MEDLINE, Ovid EMBASE, CINAHL, PubMed, Web of Science and the Cochrane Database of Systematic Reviews were searched from inception up to 23 November 2018. Randomized controlled trials and observational studies were included in the search. Eligible studies reported on the impact of sex-matched compared to sex-mismatched RBC transfusion on recipient mortality. Two investigators independently extracted data and assessed study quality. A three-level meta-analytic model was applied to emphasize the unknown dependence among the effect sizes.

Results: Five retrospective observational studies (n = 86 737) were included; no RCTs were found. Sex-mismatched RBC transfusions were associated with a higher risk of death compared with sex-matched transfusions (pooled hazard ratio [HR]: 1·13; 95% confidence interval [CI]: 1·02-1·24). In the subgroup of cardiovascular surgery (n = 57 712), there was no significant increase in mortality with sex-mismatched transfusions (pooled HR: 1·08; 95% CI: 0·95-1·22). The data were prone to confounding, selection bias and reporting bias. Certainty of the evidence was very low.

Conclusion: Sex-mismatched RBC transfusions were associated with an increased risk of death in this pooled analysis. However, the certainty of the evidence was very low from observational studies. The need to match donor and recipient sex for transfusions requires further investigation because of the potential widespread impact.
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http://dx.doi.org/10.1111/vox.12783DOI Listing
July 2019

Timeline of heparin-induced thrombocytopenia seroconversion in serial plasma samples tested using an automated latex immunoturbidimetric assay.

Int J Lab Hematol 2019 Aug 3;41(4):493-502. Epub 2019 May 3.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

Introduction: HIT is caused by platelet-activating IgG that recognize multimolecular PF4/heparin complexes. HIT antibodies are generally detectable by PF4-dependent enzyme immunoassay (EIA) and by platelet serotonin-release assay (SRA) at the beginning of the HIT-related platelet count fall. We determined whether an automated immunoassay for HIT, the latex immunoturbidimetric assay (LIA), also detects antibodies early during the course of HIT. The LIA was also used to evaluate a patient with putative SRA-negative HIT.

Methods: We evaluated the timing and magnitude of LIA reactivity in serial plasma samples obtained from 19 SRA-positive patients (17 with abnormal platelet count changes indicating HIT; two with subclinical seroconversion) and one putative SRA-negative HIT patient, all obtained from patients who participated in a clinical trial of heparin thromboprophylaxis. We determined LIA status at the onset of the HIT-related platelet count fall.

Results: The LIA was positive in all 19 SRA-positive patients (median value, 7.3 U/mL [range, 1.2-35.5]; cutoff, 1.0 U/mL); for all 13 evaluable patients for whom an informative plasma sample was available at (or shortly before) the onset of the HIT-related platelet count fall, LIA reactivity was positive. Heterogeneity in seroconversion using the LIA was observed; some patients exhibited gradual increases in reactivity, whereas other patients showed rapid increase in reactivity over a few days. The single clinical trial patient who met clinical-pathological criteria for "SRA-negative HIT" tested LIA-positive.

Conclusion: The LIA detects HIT antibodies at the beginning of the HIT-associated platelet count fall. The LIA was also positive in a patient with SRA-negative HIT.
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http://dx.doi.org/10.1111/ijlh.13031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850468PMC
August 2019

Postnatal intervention for the treatment of FNAIT: a systematic review.

J Perinatol 2019 10 10;39(10):1329-1339. Epub 2019 Apr 10.

Division of Haematology/Oncology, CHU Sainte-Justine, University of Montreal, Montreal, Canada.

Objective: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with life-threatening bleeding. This systematic review of postnatal management of FNAIT examined transfusion of human platelet antigen (HPA) selected or unselected platelets, and/or IVIg on platelet increments, hemorrhage and mortality.

Study Design: MEDLINE, EMBASE and Cochrane searches were conducted until 11 May 2018.

Result: Of 754 neonates, 382 received platelet transfusions (51%). HPA-selected platelets resulted in higher platelet increments and longer response times than HPA-unselected platelets. However, unselected platelets generally led to sufficient platelet increments to 30 × 10/L, a level above which intracranial hemorrhage or other life-threatening bleeding rarely occurred. Platelet increments were not improved with the addition of IVIg to platelet transfusion.

Conclusion: Overall, HPA-selected platelet transfusions were more effective than HPA-unselected platelets but unselected platelets were often effective enough to achieve clinical goals. Available studies do not clearly demonstrate a benefit for addition of IVIg to platelet transfusion.
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http://dx.doi.org/10.1038/s41372-019-0360-7DOI Listing
October 2019

The association between platelet transfusions and mortality in patients with critical illness.

Transfusion 2019 06 1;59(6):1962-1970. Epub 2019 Apr 1.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Platelet (PLT) transfusions are frequently administered in the setting of critical illness but their clinical impacts remain unknown. This study examined the association between PLT transfusions and death in a large intensive care unit (ICU) patient population.

Study Design And Methods: Using a transfusion registry spanning 2008 to 2015, this study assessed effect of in-ICU PLT transfusions on ICU and in-hospital mortality using a stratified, time-dependent Cox proportional hazards model adjusted for illness severity, thrombocytopenia, and other confounders. Patients with known malignancy were excluded. Exposure to PLT transfusions were analyzed dichotomously (ever or never transfused) and continuously (number of transfusions). Medical, general surgery, and cardiac surgery subgroups were analyzed separately.

Results: Overall 32,842 adult patients were admitted to ICU, and 4927 patients received PLT transfusion(s). Crude in-ICU and in-hospital mortality were higher for PLT-transfused patients compared to nontransfused patients (9.2% vs. 6.7% and 12.3% vs. 9.3%, respectively). After confounders were adjusted for, PLT transfusions (ever vs. never) were not associated with increased mortality in ICU (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.60-1.02; p = 0.06) or in hospital (HR, 0.89; 95% CI, 0.68-1.09; p = 0.41). Continuous exposure analysis also showed no association between PLT transfusions and death. PLT transfusions have a protective effect on in-hospital mortality in the subgroup of general surgery patients (HR, 0.71; 95% CI, 0.51-0.99; p = 0.04; ever or never analysis).

Conclusion: Platelet transfusions were not associated with increased risk of death in critically ill patients. Further studies are required to identify subgroups for which PLT transfusions may be beneficial.
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http://dx.doi.org/10.1111/trf.15277DOI Listing
June 2019

Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.

Br J Haematol 2019 05 3;185(3):549-562. Epub 2019 Mar 3.

University of Toronto, Toronto, Canada.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.
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http://dx.doi.org/10.1111/bjh.15813DOI Listing
May 2019