Inherited Platelet Function Disorders Research Articles

ISTH bleeding assessment tool and platelet function analyzer in children with mild inherited platelet function disorders.

To evaluate the diagnostic performance of platelet function analyzer (PFA) and The International Society on Thrombosis and Hemostasis bleeding-assessment-tool (ISTH-BAT) in detecting mild inherited platelet function disorders (IPFDs) in children with suspected bleeding disorders. Prospective single-center diagnostic study including consecutive patients <18 years with suspected bleeding disorder and performing a standardized workup for platelet function defects including ISTH-BAT, PFA, platelet aggregation testing, blood smear-based immunofluorescence, and next-generation sequencing-based genetic screening for IPFDs. We studied 97 patients, of which 34 von Willebrand disease (VWD, 22 type-1, 11 type-2), 29 IPFDs (including delta-/alpha-storage pool disease, Glanzmann thrombasthenia, Hermansky-Pudlak syndrome) and 34 with no diagnosis. In a model combining PFA-adenosine diphosphate (ADP), PFA-epinephrine (EPI), and ISTH-BAT overall performance to diagnose IPFDs was low with area under the curves of 0.56 (95% CI 0.44, 0.69) compared with 0.84 (95% CI 0.76, 0.92) for VWD. Correlation of PFA-EPI/-ADP and ISTH-BAT was low with 0.25/0.39 Spearman's correlation coefficients. PFA were significantly prolonged in patients with VWD and Glanzmann thrombasthenia. ISTH-BAT-scores were only positive in severe bleeding disorders, but not in children with mild IPFDs or VWD. Neither ISTH-BAT nor PFA or the combination of both help diagnosing mild IPFDs in children. PFA is suited to exclude severe IPFDs or VWD and is in this regard superior to ISTH-BAT in children.

High annualized bleeding rates in pediatric patients with inherited platelet function disorders.

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Rare bleeding disorders: Advances in management

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Association of laboratory test results with the bleeding history in patients with inherited platelet function disorders (the Bleeding Assesment Tool - LABoratory tests substudy): communication from the Platelet Physiology ISTH-SSC

BackgroundIn hemophilia and von Willebrand disease, the degree of alteration of laboratory assays correlates with bleeding manifestations. Few studies have assessed the predictive value for bleeding of laboratory assays in patients with inherited platelet function disorders (IPFDs). ObjectivesTo assess whether there is an association between platelet function assay results and bleeding history, as evaluated by the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT). MethodsCenters participating in the international ISTH-BAT validation study were asked to provide results of the diagnostic assays employed for the patients they enrolled, and the association with the individual patients’ bleeding score (BS) was assessed. ResultsSixty-eight patients with 14 different IPFDs were included. Maximal amplitude of platelet aggregation was significantly lower in patients with a pathologic BS and correlated inversely with the BS, a finding largely driven by the subgroup of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency; after their exclusion, TRAP-induced aggregation remained significantly lower in patients with a pathologic BS. Bleeding time was significantly more prolonged in patients with a high BS than in those with a normal BS (27.1 ± 6.2 minutes vs 15.1 ± 10.6 minutes; P < .01). Reduced α-granule content was significantly more common among patients with a pathologic BS than among those with a normal BS (80% vs 20%; P < .05). Receiver operating characteristic curve analysis revealed a significant discriminative ability of all the aforementioned tests for pathologic BS (P < .001), also after exclusion of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency. ConclusionThis study shows that altered platelet laboratory assay results are associated with an abnormal ISTH-BAT BS in IPFD.

Understanding Natural History of Common Inherited Platelet Function Disorder (IPFD) Patients: An Indian Study

Background : Inherited platelet function disorders (IPFDs) are less well studied in a resource poor country in comparison to hemophilia and other bleeding disorders.With high rates of consanguinous marriages in some of the communities in India, Glanzmanns thrombasthenia (GT) and Bernard soulier syndrome (BSS) are the two platelet function disorders that are commonly diagnosed. There is no data on the nature of bleeding, mode of treatment, mortality as well as quality of life (QoL) in these conditions. Aim : To understand clinical manifestations, treatment, quality-of-life (QoL), mortality and other details in GT and BSS patients. Methods : This is a retrospective, non-interventional, observational single center data collection study.Subjects were eligible to participate, if they had confirmed reports of laboratory diagnosis of GT or BSS by both platelet aggregometry and flow cytometry studies. Data collected were demographics, medical history, co-morbidities (HIV, HCV, HBV), detailed treatment/product(s) usage, bleeding events, surgical procedures, and other adverse events. It also included patient-reported outcome questionnaires regarding health-related quality of life (HRQoL) using SF-36 and EQ-5D instruments. All data were entered into electronic case report forms by the laboratory personnel. Results : Sixty one ( GT 50, BSS 11) patients participated in the present study; 31 were males and 30 females. 43 were pediatric patients and 18 adults. Seventeen patients were diagnosed at birth and 10 patients were diagnosed beyond the age of 10 years. Forty four patients (72%) had parental consanguinity. Thirteen patients ( BSS 8, GT 5) did not have any major bleeding manifestations which required treatment. In the remaining patients, the median ABR was 10 ( range 2.5 - &amp;gt;75). The median ISTH BAT score was 10 (range 1-26.)The bleeding manifestations included epistaxis (61%), ecchymosis (58%) , gum bleed (48%), gastrointestinal bleed (28%), soft tissue bleed (23%), hematuria (8%), joint bleed (3%) and intracranial bleed ( 3%). Heavy menstrual bleed (HMB) was the primary bleeding manifestation in all females in the reproductive age group. Four patients were diagnosed following circumcision. Treatment strategies for bleeding events included antifibrinolytic agents alone (26%), platelet transfusion (43%), or whole blood and fresh frozen plasma (39%). Antifibrinolytic agents were also used as adjunct agents with platelet transfusion in majority of the patients. None of the patients were on recombinant activated FVIIa. Overall 8 deaths were reported due to bleeding in these 61 families during the last 10 years, the cause of death mainly being non-availability of treatment products. The self- reported median EQ-5D health score was 82.5 ( range 40-100) Figure 1 shows the detailed EQ-5D analysis in these 61 patients Conclusion : Present study provides detailed information of GT and BSS and its impact throughout life. A wide variation in clinical manifestations and disease outcomes was observed, the major attributing factor may possibly be socioeconomic factor which includes access to clinical resources and treatment products for bleed management. Unlike hemophilia, GT and BSS patients do not have the privilege of prophylactic treatment in our country, but there is a need for optimal disease management to normalize both physical and psychosocial outcomes. More such studies will add to an increased understanding of critical issues in these

PB1382 Inherited Platelet Function Disorder in Pediatric Patient with Identified CalDAG-GEFI Deficiency

PB1382 Inherited Platelet Function Disorder in Pediatric Patient with Identified CalDAG-GEFI Deficiency

Psychological complications among patients with congenital bleeding disorders.

Congenital bleeding disorders (CBDs), including inherited platelet function disorders and rare and common bleeding disorders, are a heterogeneous group of bleeding disorders with a wide range of clinical presentations, including psychological complications. Due to the chronic nature of CBDs, psychological complications are relatively common in these patients, which can affect treatment adherence, quality of life, and even the frequency of bleeding episodes. Chronic pain causes many psychological problems in CBDs, disrupting their social interactions, affecting all aspects of their lives, including their emotional functioning and behavior, and eventually leading to social exclusion. About one-third of patients with severe hemophilia A suffer from anxiety, 64% from depression, and 60% from other minor psychological complications such as withdrawal/depression, anxiety/depression, attention problems, and emotional problems. Anxiety, depression, and uncontrolled pain interfere with treatment adherence. For this reason, psychological interventions are needed in people with CBDs. Psychological interventions increase quality of life and treatment adherence. Therefore, early recognition of psychological complications in CBD patients may increase treatment adherence, leading to a reduction in bleeding episodes and thus an improvement in quality of life.

The Promise of Next-Generation Sequencing in Improving the Diagnosis of Rare Genetic Disorders in Developing Countries

Introduction Genetic testing is frequently required for aiding and confirming the diagnosis, selecting treatment and predicting prognosis in patients with hematological disorders (1). However, large-scale genetic studies based on whole exome or genetic panel sequencing have not been a primary focus of developing countries due to lack of awareness, a dearth of genetic testing laboratories in clinical facilities, and the limited financial resources of affected families. As a result, the underlying genetic patterns in these patients often go undetected. Nevertheless, these countries constitute a rich source of clinical data with atypical phenotypes and novel mutations due to large family sizes, inter-family marriages, and potential founder effects (2). These genotype and phenotype data are worth being presented in the international data repositories for better identification of pathogenic variants in this population (3). Armed Forces Bone Marrow Transplant Centre (AFBMTC) is the country's largest hospital providing clinical hematology and stem cell transplantation services to a catchment area of over 560,000 Km2. We sought to identify underlying genetic causes of various difficult-to-diagnose rare hematological disorders with heterogenous/overlapping symptoms and challenging clinical presentation using next-generation sequencing (NGS). Materials and Methods Peripheral blood samples from 33 individuals with diverse hematological diseases were sent to Invitae Corporation (USA) or Centogene GmbH (Germany) for panel sequencing or whole exome sequencing, respectively. These samples were from patients who were difficult-to-diagnose, required risk stratification or genetic testing for selecting appropriate treatment. Results Whole exome sequencing or panel sequencing was performed in a cohort of 33 patients with various hematological disorders (figure 1). A total 115 variants were identified in these patients including 15 pathogenic variants (13%), 7 likely pathogenic variants (6%), 82 variants of uncertain significance-VUS (71%), 9 benign variants (7.8%) and 1 increased risk allele variant (0.86%). A total of 42 variants were found in musculoskeletal disorders panel, 20 in primary immunodeficiency panel, 11 each in bone marrow failure syndrome panel and dyskeratosis congenita panel, 9 in comprehensive deafness panel and 9 in hereditary hemolytic anemia panel among others. The most frequent diagnosis in our cohort was inherited bone marrow failure syndromes (27.3%), followed by hemolytic anemias (15.2%), immunodeficiency disorders (12.2%), inherited platelet function disorders (12.2%), myelofibrosis disorders (12.2%), skeletal disorders (12.2%) and miscellaneous disorders (9.1%). Patients clinical and demographic characteristics are summarized in table 1. Conclusion Use of high-throughput NGS in our clinical hematology setting has proven to be useful in identifying genetic variants for accurate diagnosis, selecting appropriate therapies, and predicting prognosis. We intend to develop a genetic facility that will provide genetic testing and identify ways to make it more accessible for people of all socioeconomic backgrounds. A second objective is establishing the prevalence of most frequent genetic disorders in the country. The high number of variants of uncertain significance (VUS) is most likely driven by a lack of sufficient population-based genetic data and proof of functional impact, though the patients identified having VUS were phenotypically disease presenting. Thus, supporting the hypothesis that these VUS may eventually be classified as pathogenic after appropriate testing on larger scales and animal models. To achieve a dependable and precise categorization of VUS, we plan to include functional genomics in our research focus to support the clinical database of this region. 1. Haferlach TJh. The time has come for next-generation sequencing in routine diagnostic workup in hematology. 2021;106(3):659. 2. MALTESE P, Poplavskaia E, Malyutkina I, Sirocco F, Bonizzato A, Capodicasa N, et al. Genetic tests for low-and middle-income countries: a literature review. 2017;16(1). 3. Gutierrez-Rodrigues F, Calado RTJH, Transfusion, Therapy C. The interpretation of rare or novel variants: Damaging vs. disease-causing. 2018;40:3-4. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The utility of flow cytometric platelet forward scatter as an alternative to mean platelet volume

The use of mean platelet diameter (MPD) to classify inherited thrombocytopenia (IT) has been demonstrated in several studies. Alternatively, the mean platelet volume (MPV) may be used, but in macrothrombocytopenia this may not be available. We hypothesized that platelet forward scatter (FSC) measurements using flow cytometry may be used for the size-based classification of IT. The study aimed to assess the ability of platelet FSC to measure platelet size and whether it could be used as an alternative to the MPD or MPV. Blood samples were obtained from individuals undergoing investigation for inherited platelet function disorders (IPFD, n = 40) or platelet number disorders (IPND, n = 46). A hematology analyzer was used to obtain MPV and platelet counts, flow cytometry to measure platelet FSC and ImageJ software to measure MPD from stained blood smears. The International Society of Thrombosis and Hemostasis (ISTH) Bleeding Assessment Tool (BAT) was used to calculate bleeding scores. Twenty-nine(63%) of IPND patients had an MPV that could not be reported. A significant correlation to platelet FSC was found to the MPD (p < .0001) and MPV (p < .0001) and an inverse correlation with platelet count (p < .0001). No significant correlation was found between FSC and bleeding history. In conclusion, platelet FSC is an alternative to MPV and may be used in macrothrombocytopenia where the MPV is not recorded

How I manage pregnancy in women with Glanzmann thrombasthenia

AbstractGlanzmann thrombasthenia (GT) is a rare inherited platelet function disorder caused by a quantitative and/or qualitative defect of the αIIbβ3 integrin. Pregnancy and delivery are recognized risk periods for bleeding in women with GT. The newborn may also be affected by fetal and neonatal immune thrombocytopenia induced by the transplacental passage of maternal anti-αIIbβ3 antibodies, which can lead to severe hemorrhage and fetal loss. Pregnancy in women with GT thus requires a multidisciplinary approach, including prepregnancy counseling and a treatment plan for delivery for both the mother and child. In this article, we summarize the current knowledge on pregnancy in women with GT and describe how we manage this severe platelet disorder in our clinical practice.

Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review.

AimCurrently, it is unknown which patient‐reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient‐reported outcomes and their measurement methods in autosomal inherited bleeding disorders.MethodsThe Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient‐reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included.ResultsTwenty‐one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self‐developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health‐related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health‐related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain.ConclusionPatients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.

Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG).

The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of ITGB3 was the most common, followed by c.2333A>C (p.Gln778Pro) of ITGB2B. Known variants of GT, including c.917A>C (p.His306Pro) of ITGB3 and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of ITGA2B, were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of ITGB3 and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of ITGA2B, were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel RASGRP2 variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs.

Mutations in RASGRP2 gene identified in patients misdiagnosed as Glanzmann thrombasthenia patients

IntroductionGlanzmann thrombasthenia (GT) is a severe inherited platelet function disorder (IPFD), presenting with bleeding diathesis and impaired platelet aggregation, is caused by mutations in the genes ITGA2B or ITGB3. AimWe aimed to study the genetic cause of IPFD mimicking GT. MethodsDuring 2017–2019, 16 patients were referred to our tertiary center with bleeding symptoms, impaired platelet aggregation and normal platelet count and size. ResultsUsing flow cytometry, 13/16 patients were diagnosed with GT, yet three patients displayed normal surface expression of the integrins αIIbβ3 and αvβ3, as well as normal integrin αIIbβ3 activation following incubation with the activating monoclonal antibody anti-LIBS6, while platelet activation following ADP or epinephrine was impaired. Whole exome sequencing detected 2 variants in RASGRP2 gene in all 3 patients. DiscussionBoth RASGRP2 mutations predicted frameshift, premature stop codon (p. I427Mfs*92 and p. R494Afs*54, respectively) and truncated calcium-sensing guanine nucleotide exchange factor [CalDAG-GEFI]- the major signaling molecule that regulates integrin-mediated aggregation and granule secretion, causing IPFD-18. ConclusionPatients who suffer from bleeding diathesis without immune dysregulation, may be mistakenly diagnosed as GT. Further studies are required to confirm the diagnosis of specific IPFD.

Fully automated light transmission aggregometry on a disc for platelet function tests.

Platelet function tests, a group of assays that measure the ability of platelets to aggregate and promote clotting in a sample of blood, are performed in various medical fields to assess inherited platelet function disorders and monitor antiplatelet therapies. Light transmission aggregometry (LTA) is considered the gold standard for platelet function assessment. However, the lack of a standardized protocol is a major drawback when applied at the point of care. Moreover, it is a time-consuming and labor-intensive assay that requires a large volume of blood. Here, we describe the design, fabrication, and operation of a centrifugal microfluidic disc that can perform a fully automated LTA assay from a small volume of a whole blood sample (<1 mL), achieving highly reproducible results (3.2% coefficient of variation) within a short period (<25 min). The assays performed with this device yield more precise and accurate results than traditional LTA because of the automation of the reaction steps, minimal human operation, robust detection strategy via the distinctive structure of the microfluidic chamber, and quick analysis that minimizes the adverse effects of platelet instability.

Acquired Glanzmann thrombasthenia: a rare disorder

Qualitative platelet function defects may be congenital, e.g., Glanzmann thrombasthenia, or acquired. Acquired platelet function disorders are more common than reported. Glanzmann thrombasthenia, an inherited platelet function disorder, is caused by mutations in the ITGA2B and ITGB3 genes encoding the αIIbβ3 integrin. An acquired form of GT is also seen, which is caused by antibodies to platelet integrin αIIbβ3. This affects fibrinogen binding and blocks platelet aggregation. These patients have low platelet count with a moderate-to-severe bleeding tendency, while some patients may have normal platelet counts. It is commonly found in association with autoimmune disorders, hematological malignancies, and infections. Glanzmann thrombasthenia-like state can also be seen in immune thrombocytopenic purpura (ITP) due to presence of antibodies to αIIbβ3. These patients present with severe bleeding even with mild thrombocytopenia. We describe a patient of ITP with borderline low platelet count and severe bleeding, who posed a diagnostic challenge. However, an accurate diagnosis and suitable management helped to avoid catastrophic bleeding.

Platelet function testing in patients with post-operative tonsillectomy bleeding may be a useful early identifier of inherited platelet function disorders.

Post-tonsillectomy bleeding is the most frequent complication of tonsillectomy. Inherited platelet function disorders have an estimated prevalence of 1 per cent. Any association between post-tonsillectomy bleeds and undiagnosed inherited platelet function disorders has not been investigated before. To assess the prevalence of inherited platelet function disorders in a cohort of post-tonsillectomy bleed patients. An observational cohort study was conducted using hospital digital records. Platelet function analyser 100 ('PFA-100') closure time was tested on post-tonsillectomy bleed patients who presented to hospital. Between 2013 and 2017, 9 of 91 post-tonsillectomy bleed patients who underwent platelet function analyser 100 testing (9.89 per cent) had positive results. Five patients (5.49 per cent) had undiagnosed inherited platelet function disorders. Four patients had false positive results secondary to a non-steroidal anti-inflammatory drug effect (specificity of 95.3 per cent) proven by repeat testing six weeks later, off medication. The false negative rate was 0 per cent. The prevalence of inherited platelet function disorders in our post-tonsillectomy bleed cohort is five-fold higher than in the general population. Platelet function analyser 100 testing when patients present with a post-tonsillectomy bleed allows management of their inherited platelet function disorder.

Outpatient Management of Heavy Menstrual Bleeding in Adolescent and Young Women with Inherited Platelet Function Disorders.

To assess the treatment patterns and efficacy of hormonal (HM) and non-HM (NHM) management of heavy menstrual bleeding (HMB) in young women with inherited platelet function disorders (IPFDs). A retrospective chart review was performed of outpatient treatment of HMB in female patients age 9-25years who were diagnosed with IPFDs and referred to gynecology and/or hematology at a tertiary care hospital between 2006 and2018. The study sample was identified using billing codes for IPFDs. Data on HM and NHM treatments and outcomes over a one- to two-year period were collected. Initial treatment was defined as the first treatment prescribed after referral. Descriptive statistics, Pearson χ2, and t tests were used for analysis. Treatment failure was defined as a change in treatment method because of continued bleeding. Thirty-four girls met inclusion criteria. After their initial visit, 19/34 (56%) were treated with HM, 12/34 (35%) with NHM, 2/34 (6%) with a combination of methods, and 1/34 (3%) were untreated. Initial treatment failed in 19/34 (56%) and those patients subsequently required a mean of 2 additional treatments during follow-up. Of the 34 included, 6/34 (18%) remained uncontrolled despite numerous treatment changes and 2/34 (6%) because of noncompliance. When control was achieved, 7/26 (27%) of patients were receiving combined oral contraceptives and 6/26 (23%) desmopressin acetate. HMB in girls with IPFDs can be difficult to control despite ongoing follow-up and treatment changes. Although the most effective treatment for HMB in young women with IPFDs was not identified, these findings will help providers and patients with setting expectations. Prospective studies are needed to develop recommendations on best practices.

Platelet immunophenotyping in health and inherited bleeding disorders, a review and practical hints.

Inherited platelet function disorders are rare hemorrhagic diseases. The gold standard for their exploration is optical aggregometry; however, investigations by flow cytometry (FCM) are being increasingly used. In this review, the physiology of platelets is first recalled, setting the stage for the compartments of platelets that can be apprehended by specific and appropriate labeling. As this requires some pre-analytical precautions and specific analytical settings, a second part focuses on these characteristic aspects, based on literature and on the authors' experience in the field, for qualitative or quantitative explorations. Membrane labeling with antibodies to CD42a or CD41, respectively, useful to assess the genetic-related defects of Glanzmann thrombocytopenia and Bernard Soulier syndrome are then described. Platelet degranulation disorders are detailed in the next section, as they can be explored, upon platelet activation, by measuring the expression of surface P-Selectin (CD62P) or CD63. Mepacrin uptake and release after activation is another test allowing to explore the function of dense granules. Finally, the flip-flop anomaly related to Scott syndrome is depicted. Tables summarizing possible FCM assays, and characteristic histograms are provided as reference for flow laboratories interested in developing platelet exploration.

Current Knowledge on Inherited Platelet Function Disorders

Current Knowledge on Inherited Platelet Function Disorders

Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC

BackgroundCareful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH‐BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. ObjectivesThe aim of the present study was to test the utility of the ISTH‐BAT in a large cohort of patients with a well‐defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type‐1 von Willebrand disease (VWD‐1) and one of healthy controls (HC). Patients/MethodsWe enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. ResultsIPFD patients had significantly higher bleeding score (BS; median 9) than VWD‐1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2).The ISTH‐BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD‐1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC. ConclusionsThe ISTH‐BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD‐1. Therefore, the ISTH‐BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.