Clinical and laboratorial characterization of a cohort of patients with hereditary platelet disorders

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Diagnosing IPDs is challenging which may results in delays, misdiagnosis and unappropriated treatment. In low and middle-income countries data on these disorders are scarce. Here, we describe a cohort of IPD patients at a reference center in Brazil. Methods: A descriptive analysis was conducted on patients with suspected or diagnosed IPDs at the Thrombosis and Hemostasis outpatient clinic of the Hospital das Clinicas, University of São Paulo, Brazil. From 857 patients identified between 1998 and 2023, 60 met the eligibility criteria for suspected or confirmed IPDs. Patients with acquired causes of platelet dysfunction were excluded. Results: The cohort comprised 60 patients, 65% with IPFDs and 35%, IPNDs. Women were 75%, with a median age of 48 years. IPDs were suspected based on clinical history, family history, and laboratory tests. In the IPND group, 62% had a family history of thrombocytopenia. In the IPFD group, family history was positive in 51% of cases. Previous misdiagnosis included ITP (immune thrombocytopenia) and von Willebrand disease. The bleeding phenotype, assessed using the ISTH BAT (Bleeding Assessment Tool) score, showed a median score of 6, with IPNDs scoring lower than IPFDs. Conclusions: Identifying IPDs is essential for proper treatment and follow-up. This study emphasizes the need for careful assessment of the familial history, bleeding risk, platelet count, morphology and function in diagnosing IPDs, particularly in low resource settings without access to advanced genetic testing. thrombocytopenia inherited coagulation disorders platelets epidemiology diagnosis Figures Figure 1 Figure 2 Introduction Inherited platelet disorders (IPDs) encompass a diverse range of conditions characterized by altered platelet function (inherited platelet function disorders, IPFDs) and/or reduced platelet counts (inherited platelet number disorders, IPNDs)[ 1 – 3 ]. These diseases are rare, with an estimated prevalence of 2–3 cases per 100,000 people[ 3 , 4 ]. Clinical presentations vary widely, with patients experiencing bleeding episodes ranging from mild to severe, sometimes accompanied by other findings such as decreased platelet counts, abnormal platelet morphology, syndromic features, or a predisposition to other systemic diseases[ 5 ]. Their pathophysiology is still being uncovered. With advancing genetic mapping tools, many new entities are being identified. Today, 60 distinct IPDs and 75 related genes have been recognized[ 5 , 6 ]. Diagnosing IPDs is challenging and often leads to delays or misdiagnosis. Diagnostic assessments involve evaluating the location, triggers, and severity of bleeding episodes, concurrent syndromic features and relevant family history. Initial evaluations include examining platelet count and morphology. Additional tests, such as platelet aggregation, immunophenotyping, and electron microscopy, may be utilized to assess platelet function. Genetic mapping can aid in diagnosis by identifying mutations associated with inherited platelet disorders, though its accessibility is often limited[ 7 , 8 ]. Lack of knowledge about IPD, combined with the heterogeneity of clinical manifestations and the difficulty of laboratory confirmation, can lead to delays in diagnosis and subsequently in treatment. Accurately identifying and characterizing these disorders is crucial for providing appropriate treatment, genetic counseling, and follow-up, especially considering their association with systemic diseases and neoplasia[ 7 , 8 ]. Most of the existing data on these diseases is derived from registries in North America and Europe. In low- and middle-income countries, such as Brazil, there is a lack of data describing the characteristics of this population and the challenges faced in diagnosing this group of diseases, particularly in the context of the public health system and its limited resources. In this context, this study describes a cohort of IPD patients followed at a reference center in Brazil. The objective is to contribute to the limited existing body of evidence on the clinical presentation of these diseases in low- and middle-income countries, with the ultimate goal of promoting awarenesses of IPDs and their diagnosis in these countries. Methods We conducted a retrospective descriptive analysis of the cohort of patients with suspected or diagnosed IPDs being followed at the Thrombosis and Hemostasis outpatient clinic of the Hospital das Clínicas of the Faculty of Medicine, University of São Paulo (HCFMUSP), Brazil. To identify this population, we searched our thrombosis and hemostasis outpatient clinic database for the following diagnoses: unexplained thrombocytopenia, unexplained platelet dysfunction, unexplained bleeding, storage pool disease, Glanzmann thrombasthenia, Bernard-Soulier syndrome (BS) and May-Hegglin anomaly. We identified 857 patients in our database from 1998 to 2023. An individual analysis of the medical records was then performed based on the following eligibility criteria. Patients with a confirmed or suspected diagnosis of inherited platelet disorder were included. Due to the unavailability of some necessary diagnostic tests (electron microscopy, genetic mapping), we considered as suspected those patients who had persistent thrombocytopenia since childhood without response to previous treatments, a suggestive family history, or increased bleeding associated with altered platelet aggregation and/or secretion tests. Patients with acquired causes of platelet dysfunction or thrombocytopenia were excluded, including those related to medications, infections, hypersplenism, immune thrombocytopenia, and thrombocytopenias that reversed during follow-up. This study was approved by the Research Ethics Committee of HCFMUSP (CAAE 67501923.7.0000.0068). Results 857 patients, 217 were excluded due to loss to follow-up, 319 due to lack of electronic records and 261 did not meet the eligibility criteria, of whom 130 (50%) had a diagnosis of ITP (Figure 1). This figure illustrates the patient selection and reasons for exclusion . ITP: immune thrombocytopenia; MDS: Myelodysplastic syndrome; AA: Aplastic anemia; DIC: Disseminated intravascular coagulation. The final cohort comprised 60 patients, 39 (65%) with IPFDs and 21 (35%) with IPNDs. There was a predominance of women (75%), with a median age of 48 years. The racial distribution was 42% white, 42% mixed-race and 16% black, without differences between the subgroups (Table1). Table 1 Clinical and laboratory features of the IPD cohort Variables Total (n=60) IPND (n=21) IPFD (n=39) Woman , n (%) 45 (75) 13 (62) 32 (82) Race, n (%) White 25 (42) 8 (38) 17 (44) Black 10 (16) 2 (10) 8 (20) Mixed Race 25 (42) 11 (52) 14 (36) ISTH BAT score a , median ± (IQR) 6.0 (3.0-11.0) 3.5 (1.8-4.3) 10.0 (6.0-13.0) Highest platelet count during follow-up, 1000/mm 3 median ± (IQR) 178 (105-316) 108 (85-125) 279 (195-369) Lowest platelet count during follow-up, 1000/mm 3 median ± (IQR) 90 (47-153) 56 (26-63) 132 (96-182) Highest MPV during follow-up (fL) b , median ± (IQR) 11.5 (10.4-14.3) 14.1 (13.4-16.0) 11.1 (10.2-11.7) Platelet aggregation test, n (%) Patients with a platelet aggregation test 34 (57) 9 (43) 25 (64) Patients with abnormal platelet aggregation results 27 (79) 3 (33) 24 (96) Consistent abnormalities c 19 (70) 2 (67) 17 (71) Inconsistent abnormalities c 8 (30) 1 (33) 7 (29) Platelet secretion assay, n (%) Patients with a platelet secretion assay 16 (27) 2 (10) 14 (39) Patients with abnormal results 7 (44) 1 (50) 6 (43) Immunophenotyping test, n (%) Patients with an immunophenotyping test 27 (45) 6 (29) 21 (54) Patients with abnormal immunophenotyping test results 15 (55) 0 15 (71) Abbreviations: n: number; IPND: Inherited platelet number disorder; IPFD: Inherited platelet function disorders; IQR: Interquartile range; ISTH BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool; MPV: mean platelet volume. a BAT score was available for 57 (95%) IPD patients. b The local MPVreference values range from 6.5 to 12.5 fl. c For patients with more than one aggregation test , we considered as “consistent abnormalities” when all the tests performed showed the same aggregation abnormality and “inconsistent abnormalities” when one or more results were discordant. The suspicion of IPDs was based on factors obtained from the clinical history and laboratory tests. In cases where patients exhibited thrombocytopenia, IPNDs were suspected due to a positive family history of thrombocytopenia, which was present in 13 out of 21 patients (62%), or after the diagnosis of immune thrombocytopenia (ITP) was excluded. A diagnosis of ITP was excluded based on the observation of long-standing, stable thrombocytopenia in the absence of a response to previous therapeutic interventions. In IPND cohort, 8 patients (38%) received treatment for ITP without response, including corticosteroids (8 patients, 38%), immunoglobulin (1 patient, 5%), immunosuppressants (1 patient, 5%) and splenectomy (2 patients, 10%). Eight patients (15%) had previously received an alternative diagnosis. One patient initially suspected of having ITP was confirmed to have MYH9-related thrombocytopenia, two cases of ITP were confirmed as Bernard-Soulier syndrome, three cases of ITP were reclassified as unspecified inherited thrombocytopenia, and two patients initially suspected of having von Willebrand disease were reclassified as unspecified inherited platelet function disorder. In the IPFD group, the family history was positive in 20 out of 39 patients (51%). Since some had concomitant thrombocytopenia, 2 patients received treatment for ITP (6%), including corticosteroids (1 patient, 3%), immunoglobulin (1 patient, 3%), immunosuppressants (1 patient, 3%) and splenectomy (1 patient, 3%). In cases where patients exhibited excessive bleeding that was disproportionate to their platelet count, in addition to ruling out von Willebrand disease and other coagulopathies, platelet function was evaluated using aggregation tests, platelet immunophenotyping, and platelet secretion test (lumiaggregometry). Abnormalities in these tests led to the suspicion or confirmation of IPFDs. Nearly all patients faced some hemostatic challenge (57 out of 60 patients, 95%), including dental extraction, endoscopic or surgical procedures. Among a total of 51 women, 23 (51%) had previous pregnancy. There was a remarkable difference between groups, with 12 out of 13 (92%) IPND women reporting previous pregnancy, but only 11 out of 32 (34%) IPFD women. The bleeding phenotype was assessed using the ISTH BAT score[9] with a median score of 6 for the entire cohort (normal value are <4 for men and <6 for women). There was also a difference between subgroups: a median of 3.5 in the IPND group and of 10 in the IPFD group (Table 1). In the entire cohort, six patients (10%) presented with associated syndromic abnormalities: three in the IPND group (15%) and three in the IPFD group (8%). The observed features included: two cases of deafness associated with nephropathy, one case of growth delay and heart disease, one case of cognitive impairment, and two cases of skeletal malformations with cognitive impairment. In the IPND group, the median highest and lowest platelet counts were 108,000/mm³ and 56,000/mm³, respectively. As expected, the IPFD group had normal or slightly reduced platelet counts, with median high and low platelet counts of 279,000/mm³ and 132,000/mm³, respectively. The median mean platelet volume (MPV) was 11.5 fL for the entire cohort, 14.1 fL for the IPND group and 11.1 fL for the IPFD group (Table 1). Platelet immunophenotyping was performed in 27 patients (45%), including six patients (29%) in the IPND group and 21 patients (54%) in the IPFD group. Of the total number of patients who underwent immunophenotyping, 15 (55%) exhibited abnormal results, all of whom were in the IPFD group (patients with a Glanzmann thrombasthenia and BS diagnosis). Platelet aggregation tests were conducted in 34 cases (57%), with nine (43%) in the IPND group and 25 (64%) in the IPFD group. Seven patients (21%) had normal results and 27 (79%) had altered platelet aggregation, however, discordant results were noted in eight (30%) of the altered tests. Lastly, platelet secretion tests were performed in 16 patients (27%), with two (10%) in the IPND group and 14 (39%) in the IPFD group (Table 1). Based on the tests performed, our cohort consists of 20 patients with confirmed diagnoses (33%) and 40 with suspected diagnoses (67%) of IPDs. Among the 20 confirmed diagnoses, there is one case in the IPND group, a MYH9 macrothrombocytopenia confirmed by a genetic panel, and 19 in the IPFD group, including 13 cases of Glanzmann thrombasthenia, five cases of Bernard-Soulier syndrome and one case of storage pool disease confirmed by electron microscopy. Of the 40 suspected diagnoses, 20 patients had unspecified IPNDs and 20 had unspecified IPFDs (Table 2). Table 2 List of final diagnosis of the IPD cohort Diagnosis IPFD N (%) Storage pool disease 1 (2) Glanzmann thrombasthenia 13 (22) Bernard-Soulier syndrome 5 (8) Unspecified inherited platelet function disorder a 20 (33) IPND N (%) MYH9 macrothrombocytopenia 1(2) Unspecified inherited thrombocytopenia b 20 (33) Legend/Abbreviations: n: number; IPND: Inherited platelet number disorder; IPFD: Inherited platelet function disorders. a Inherited platelet disorders were suspected, even in the absence of diagnostic testing, when the ISTH BAT score suggested a hemorrhagic phenotype and platelet aggregation or secretion was altered. b inherited thrombocytopeina was suspected even when diagnostic tests were not available in cases of family history, altered platelet volume, persistent long-term thrombocytopenia at stable levels, lack of response to immune thrombocytopenia treatment. A total of 47 patients (78%) received some treatment during follow-up, including 43% of patients in the IPND group and 97% in the IPFD group. The predominant treatments included the use of antifibrinolytics (73%) and platelet transfusions (55%) prior to surgical procedures or in cases of bleeding. In the IPFD group, 90% of patients received antifibrinolytic treatment and 77% received platelet transfusions, while in the IPND group, these numbers were 43% and 14% respectively. Recombinant factor VIIa (FVIIa) was used in 8 patients, all of them with Glanzmann thrombasthenia. Discussion Initially described in 1948, IPDs are a rare group of diseases, with few cohorts described in the literature. Most studies show no association with sex and these diagnoses, but some indicate a higher prevalence of IPDs among women[10–12]. In our cohort, there was also a predominance of women (75%). A possible explanation is the greater frequency of hemostatic challenges that women face, such as menstruation and delivery, allowing increased bleeding tendencies to be identified. As for the distribution of ethnicity, this data is scarce in most publications. In our clinic, there was a predominance of white and mixed-race patients and a smaller proportion of black patients. However, this ethnical distribution reflects the general Brazilian population. The diagnosis of IPDs is challenging and probably most cases remain underrecognized. Misdiagnoses are also common, often resulting in inadequate treatments[13, 14]. Among patients with IPNDs, up to 30% receive an incorrect diagnosis of ITP and are sometimes treated with prolonged corticosteroid therapy, immunosuppressants, and even splenectomy[1, 15]. In our cohort, we observed a similar occurrence, with 38% of patients in the IPND group having received prior treatment for ITP, primarily corticosteroids (38%), but also including splenectomy (10%). The IPFD group, which sometimes presents with thrombocytopenia, had a smaller proportion of patients receiving inappropriate treatments for ITP (6%), including one splenectomy (3%). When thrombocytopenia is present, it is often challenging to differentiate IPDs from ITP[13, 14]. This was represented in our cohort, as 10% of our IPD patients were earlier diagnosed with ITP. When increased bleeding occurs in the absence of thrombocytopenia, the main differential diagnosis was von Willebrand disease, with two changes in diagnosis during follow-up. A key factor in the investigation of IPDs is a family history of thrombocytopenia or increased bleeding, which was present in more than 50% of the cohort in both subgroups. Similar data have been found in other studies evaluating IPND[13, 16], with a lack of data in IPFD cohorts. Our study reinforces the importance of having this information for diagnostic suspicion of IPD. The initial division into IPND and IPFD can also help with diagnosis, it distinguishes the primary differences between the subgroups and provides guidance for subsequent steps in the diagnostic process. The IPFD group exhibits a severe hemorrhagic phenotype, showing a median ISTH BAT score of 10. Conversely, the IPND group showed a normal ISTH BAT score with a median of 3.5, with the caveat that we classified BS and Glanzmann thrombasthenia as IPFD. These data are consistent with the literature, as in the ISTH BAT SCORE validation study for the IPD population the ISTH BAT SCORE results showed a median of 9 for the IPFD group and of 2 for the IPND group[17] . Comorbidities and syndromic features, although present and warranting evaluation, accounted for 10% of our sample. It is worth noting that we evaluated only adult patients, and many syndromic patients often continue to be followed by pediatric/genetic teams. A s for laboratory propaedeutics, the platelet counts during follow up were monitored, and thrombocytopenia was present in 25% of patients with IPFD, however it was mild and disproportionate to the hemorrhagic phenotype. For the IPND group, platelet size and morphology are important components of the diagnostic workup. In our cohort, 75% of the IPND patients had altered MPV, in line with the association of these diseases with macro platelets and giant platelets, which is helpful for diagnosis. Platelet aggregation was carried out on patients with no suspicion of BS or Glanzmann's thrombasthenia, for whom direct immunophenotyping was chosen. Thus, of the 25 remaining cases of suspected IPFD, consistently abnormal platelet aggregation confirmed the diagnosis of platelet dysfunction in 17 (44%) of them. Secretion tests were altered in seven patients, detecting only one more whose aggregation test was inconsistent, but adding little information to the other six whose diagnosis was already confirmed with the aggregation test. One limitation of our study is regarding platelet morphology, as we could not obtain this data from our cohort due to the lack of reporting standardization at our institution. Another limitation relates to platelet aggregation, which yielded 30% discordant results, making diagnostic investigation more difficult. We attribute this to pre-analytical factors, which are often described in these tests. Mezanno et al. recommend the use of platelet secretion assay as a first-line investigation for IPFD but highlight the lack of standardization as a major challenge to their implementation[18]. In scenarios where resources are limited, our findings call into question the role of platelet secretion tests. When aggregation is consistent, secretion can add cost with marginal increase in diagnostic capacity. It therefore seems reasonable to focus on standardizing the platelet aggregation test and controlling pre-analytical factors. In our hospital, we do not have access to genetic mapping tools or electron microscopy; the immature platelet fraction (IPF) is still being implemented and was not used for this study. Given the available resources, we highlighted the most important points used in the investigation of IPDs and summarized them in Figure 2, as an example of a diagnostic flowchart for these conditions. Our study highlights the challenge of diagnosing IPD without genetic mapping, as two thirds of our cohorts still lacks a confirmed diagnosis. In the dashed box, we have highlighted other possible tests that were not available in our institution at the time of the study. ISTH BAT: International Society on Thrombosis and Haemostasis bleeding assessment tool; ITP: immune thrombocytopenia; MPV: mean platelet volume; NGS pannel: next generation sequencing pannel; VWF: von Willebrand factor; FVIII: factor VIII; PT: prothrombin time; aPTT: partial thromboplastin time; TT: thrombin time. Finally, regarding management, IPFD group undergo more therapeutic interventions, possibly due to a higher bleeding tendency[19], as was also observed in our cohort. Platelet transfusions and the use of antifibrinolytics were frequent in this group. On the other hand, IPNDs were treated less frequently, with transfusion triggers depending on the platelet count. Conclusion Patients with IPDs may have a higher risk of bleeding, and the vast majority will be exposed to some hemostatic challenge throughout their lives. Identifying the correct condition makes it possible to provide appropriate treatment and follow-up. In scenarios with limited resources, confirmation of the diagnosis may not always be possible. Nevertheless, the documentation of critical elements of personal and family history, the assessment of bleeding risk, and the performance of quantitative and qualitative platelet tests facilitates the identification of these patients. Our cohort serves as an example of the management of IPDs within a public healthcare system, devoid of genetic mapping exams. Moreover, the description of this cohort sheds light on the unique characteristics of these disorders within a Latin-American population. Declarations Acknowledgments Author contributions: LDVG designed the study collected data and drafted the manuscript; EO, CR and PV revised the manuscript; FAOevaluated and discussed the results and revised the manuscript; BS designed the study and the analyses and revised the manuscript. All authors contributed to the article and approved the submitted version. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Fernanda Orsi holds research grants from the National Council for Scientific and Technological Development-CNPq (grant number: 43833902018-5). Ethical Responsibilities of Authors The studies involving human participants were reviewed and approved by the CEP HCFMUSP –Campus São Paulo, Brazil. Exemption from the consent form was granted due to impossibility of contact with participants and the absence of potential harms. References Zaninetti C, Wolff M, Greinacher A (2021) Diagnosing Inherited Platelet Disorders: Modalities and Consequences. Hamostaseologie 41:475–488 Nurden P, Stritt S, Favier R, Nurden AT (2021) Inherited platelet diseases with normal platelet count: Phenotypes, genotypes and diagnostic strategy. Haematologica 106:337–350 Nurden AT, Nurden P (2020) Inherited thrombocytopenias: history, advances and perspectives. Haematologica 105:2004–2019 Balduini CL, Pecci A, Noris P (2012) Inherited thrombocytopenias: The evolving spectrum. Hamostaseologie 32:259–270 Palma-barqueros V, Revilla N, Sánchez A et al (2021) Inherited platelet disorders: An updated overview. Int J Mol Sci Megy K, Downes K, Simeoni I et al (2019) Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost 17:1253–1260 Perez Botero J, Di Paola J (2021) Diagnostic approach to the patient with a suspected inherited platelet disorder: Who and how to test. J Thromb Haemost 19:2127–2136 Lambert MP (2019) Inherited Platelet Disorders: A Modern Approach to Evaluation and Treatment. Hematol Oncol Clin North Am 33:471–487 Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D (2010) ISTH/SSC bleeding assessment tool: A standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 8:2063–2065 Sánchez-Guiu I, Antón AI, Padilla J et al (2014) Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: Results from a collaborative study. Orphanet J Rare Dis Bastida JM, Lozano ML, Benito R et al (2018) Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. Haematologica 103:148–162 Johnson B, Doak R, Allsup D et al (2018) A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia. Res Pract Thromb Haemost 2:640–652 Fiore M, Pillois X, Lorrain S, Bernard MA, Moore N, Sié P, Viallard JF, Nurden P (2016) A diagnostic approach that may help to discriminate inherited thrombocytopenia from chronic immune thrombocytopenia in adult patients. Platelets 27:555–562 Arnold DM, Nazy I, Clare R, Jaffer AM, Aubie B, Li N, Kelton JG (2017) Misdiagnosis of primary immune thrombocytopenia and frequency of bleeding: Lessons from the McMaster ITP Registry. Blood Adv 1:2414–2420 Noris P, Schlegel N, Klersy C et al (2014) Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 99:1387–1394 Lassandro G, Palladino V, Faleschini M et al (2022) CHildren with Inherited Platelet disorders Surveillance (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP). Front Pediatr Gresele P, Orsini S, Noris P et al (2020) Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC. J Thromb Haemost 18:732–739 Mezzano D, Harrison P, Frelinger AL, Mumford AD, Noris P, Lordkipanidzé M, Gresele P (2022) Expert opinion on the use of platelet secretion assay for the diagnosis of inherited platelet function disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology. J Thromb Haemost 20:2127–2135 Orsini S, Noris P, Bury L et al (2017) Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica 102:1192–1203 Additional Declarations No competing interests reported. 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14:12:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4978578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4978578/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66887130,"identity":"43fd2987-0219-49eb-9c6b-5f165f197907","added_by":"auto","created_at":"2024-10-17 13:53:55","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":97033,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1Flowchartofthestudy.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4978578/v1/94ddf6cea38e25c690c98c72.jpg"},{"id":66887124,"identity":"509c9541-6e7c-4cba-b1c4-dac576efe18a","added_by":"auto","created_at":"2024-10-17 13:53:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120772,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInstitutional work-up for the diagnosis of inherited platelet disorders\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2InstitutionalworkupforthediagnosisofIPD.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4978578/v1/60f33329fd22dde1f2a4ed66.jpg"},{"id":66898803,"identity":"61f83cc1-be2e-4717-8fe8-bd701824cde5","added_by":"auto","created_at":"2024-10-17 16:01:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":647603,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4978578/v1/1ba258a6-ad85-4eca-ad5c-20f02309be7d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and laboratorial characterization of a cohort of patients with hereditary platelet disorders","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInherited platelet disorders (IPDs) encompass a diverse range of conditions characterized by altered platelet function (inherited platelet function disorders, IPFDs) and/or reduced platelet counts (inherited platelet number disorders, IPNDs)[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These diseases are rare, with an estimated prevalence of 2\u0026ndash;3 cases per 100,000 people[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinical presentations vary widely, with patients experiencing bleeding episodes ranging from mild to severe, sometimes accompanied by other findings such as decreased platelet counts, abnormal platelet morphology, syndromic features, or a predisposition to other systemic diseases[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Their pathophysiology is still being uncovered. With advancing genetic mapping tools, many new entities are being identified. Today, 60 distinct IPDs and 75 related genes have been recognized[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDiagnosing IPDs is challenging and often leads to delays or misdiagnosis. Diagnostic assessments involve evaluating the location, triggers, and severity of bleeding episodes, concurrent syndromic features and relevant family history. Initial evaluations include examining platelet count and morphology. Additional tests, such as platelet aggregation, immunophenotyping, and electron microscopy, may be utilized to assess platelet function. Genetic mapping can aid in diagnosis by identifying mutations associated with inherited platelet disorders, though its accessibility is often limited[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLack of knowledge about IPD, combined with the heterogeneity of clinical manifestations and the difficulty of laboratory confirmation, can lead to delays in diagnosis and subsequently in treatment. Accurately identifying and characterizing these disorders is crucial for providing appropriate treatment, genetic counseling, and follow-up, especially considering their association with systemic diseases and neoplasia[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMost of the existing data on these diseases is derived from registries in North America and Europe. In low- and middle-income countries, such as Brazil, there is a lack of data describing the characteristics of this population and the challenges faced in diagnosing this group of diseases, particularly in the context of the public health system and its limited resources. In this context, this study describes a cohort of IPD patients followed at a reference center in Brazil. The objective is to contribute to the limited existing body of evidence on the clinical presentation of these diseases in low- and middle-income countries, with the ultimate goal of promoting awarenesses of IPDs and their diagnosis in these countries.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e We conducted a retrospective descriptive analysis of the cohort of patients with suspected or diagnosed IPDs being followed at the Thrombosis and Hemostasis outpatient clinic of the Hospital das Cl\u0026iacute;nicas of the Faculty of Medicine, University of S\u0026atilde;o Paulo (HCFMUSP), Brazil. To identify this population, we searched our thrombosis and hemostasis outpatient clinic database for the following diagnoses: unexplained thrombocytopenia, unexplained platelet dysfunction, unexplained bleeding, storage pool disease, Glanzmann thrombasthenia, Bernard-Soulier syndrome (BS) and May-Hegglin anomaly.\u003c/p\u003e \u003cp\u003eWe identified 857 patients in our database from 1998 to 2023. An individual analysis of the medical records was then performed based on the following eligibility criteria. Patients with a confirmed or suspected diagnosis of inherited platelet disorder were included. Due to the unavailability of some necessary diagnostic tests (electron microscopy, genetic mapping), we considered as suspected those patients who had persistent thrombocytopenia since childhood without response to previous treatments, a suggestive family history, or increased bleeding associated with altered platelet aggregation and/or secretion tests. Patients with acquired causes of platelet dysfunction or thrombocytopenia were excluded, including those related to medications, infections, hypersplenism, immune thrombocytopenia, and thrombocytopenias that reversed during follow-up.\u003c/p\u003e \u003cp\u003e This study was approved by the Research Ethics Committee of HCFMUSP (CAAE 67501923.7.0000.0068).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e857 patients, 217 were excluded due to loss to follow-up, 319 due to lack of electronic records and 261 did not meet the eligibility criteria, of whom 130 (50%) had a diagnosis of ITP (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis figure illustrates the patient selection and reasons for exclusion\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eITP: immune thrombocytopenia; MDS: Myelodysplastic syndrome; AA: Aplastic anemia; DIC: Disseminated intravascular coagulation.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The final cohort comprised 60 patients, 39 (65%) with IPFDs and 21 (35%) with IPNDs. There was a predominance of women (75%), with a median age of 48 years. The racial distribution was 42% white, 42% mixed-race and 16% black, without differences between the subgroups (Table1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 Clinical and laboratory features of the IPD cohort\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"595\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n=60)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPND (n=21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPFD (n=39)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eWoman\u003c/strong\u003e, n\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e45 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e13 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e32 (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace,\u0026nbsp;\u003c/strong\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e25 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e8 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e17 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003eBlack\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e10 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e2 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e8 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003eMixed Race\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e25 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e11 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e14 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eISTH BAT score\u003csup\u003ea\u003c/sup\u003e,\u0026nbsp;\u003c/strong\u003emedian \u0026plusmn; (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e6.0 (3.0-11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e3.5 (1.8-4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e10.0 (6.0-13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHighest platelet count during follow-up,\u0026nbsp;\u003c/strong\u003e1000/mm\u003csup\u003e3\u0026nbsp;\u003c/sup\u003emedian \u0026plusmn; (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e178 (105-316)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e108 (85-125)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e279 (195-369)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLowest\u003c/strong\u003e \u003cstrong\u003eplatelet count during follow-up,\u0026nbsp;\u003c/strong\u003e1000/mm\u003csup\u003e3\u0026nbsp;\u003c/sup\u003emedian \u0026plusmn; (IQR) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\u003cbr\u003e\n \u003cp\u003e90 (47-153)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e56 (26-63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e132 (96-182)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHighest MPV during follow-up (fL)\u003csup\u003eb\u003c/sup\u003e,\u003c/strong\u003e median \u0026plusmn; (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e11.5 (10.4-14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e14.1 (13.4-16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e11.1 (10.2-11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatelet aggregation test, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with a platelet aggregation test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e34 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e9 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e25 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with abnormal platelet aggregation results\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e27 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e3 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e24 (96)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003eConsistent abnormalities\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e19 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e2 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e17 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003eInconsistent abnormalities\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e8 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e1 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e7 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatelet secretion assay, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with a platelet secretion assay\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e16 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e2 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e14 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with abnormal results\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e1 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e6 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunophenotyping test, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with an immunophenotyping test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e27 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e6 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e21 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.05042016806723%\"\u003e\n \u003cp\u003ePatients with abnormal immunophenotyping test results\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.991596638655462%\"\u003e\n \u003cp\u003e15 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.478991596638654%\"\u003e\n \u003cp\u003e15 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: n: number; IPND: Inherited platelet number disorder; IPFD: Inherited platelet function disorders; IQR: Interquartile range; ISTH BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool; MPV: mean platelet volume.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e BAT score was available for 57 (95%) IPD patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e The local MPVreference values range from 6.5 to 12.5 fl.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u0026nbsp;\u003c/sup\u003eFor patients with more than one aggregation test\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003ewe considered as \u0026ldquo;consistent abnormalities\u0026rdquo; when all the tests performed showed the same aggregation abnormality and \u0026ldquo;inconsistent abnormalities\u0026rdquo; when one or more results were discordant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe suspicion of IPDs was based on factors obtained from the clinical history and laboratory tests. In cases where patients exhibited thrombocytopenia, IPNDs were suspected due to a positive family history of thrombocytopenia, which was present in 13 out of 21 patients (62%), or after the diagnosis of immune thrombocytopenia (ITP) was excluded. A diagnosis of ITP was excluded based on the observation of long-standing, stable thrombocytopenia in the absence of a response to previous therapeutic interventions. In IPND cohort, 8 patients (38%) received treatment for ITP without response, including corticosteroids (8 patients, 38%), immunoglobulin (1 patient, 5%), immunosuppressants (1 patient, 5%) and splenectomy (2 patients, 10%).\u003c/p\u003e\n\u003cp\u003eEight patients (15%) had previously received an alternative diagnosis. One patient initially suspected of having ITP was confirmed to have MYH9-related thrombocytopenia, two cases of ITP were confirmed as Bernard-Soulier syndrome, three cases of ITP were reclassified as unspecified inherited thrombocytopenia, and two patients initially suspected of having von Willebrand disease were reclassified as unspecified inherited platelet function disorder.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the IPFD group, the family history was positive in 20 out of 39 patients (51%). Since some had concomitant thrombocytopenia, 2 patients received treatment for ITP (6%), including corticosteroids (1 patient, 3%), immunoglobulin (1 patient, 3%), immunosuppressants (1 patient, 3%) and splenectomy (1 patient, 3%). In cases where patients exhibited excessive bleeding that was disproportionate to their platelet count, in addition to ruling out von Willebrand disease and other coagulopathies, platelet function was evaluated using aggregation tests, platelet immunophenotyping, and platelet secretion test (lumiaggregometry). Abnormalities in these tests led to the suspicion or confirmation of IPFDs.\u003c/p\u003e\n\u003cp\u003eNearly all patients faced some hemostatic challenge (57 out of 60 patients, 95%), including dental extraction, endoscopic or surgical procedures. Among a total of 51 women, 23 (51%) had previous pregnancy. There was a remarkable difference between groups, with 12 out of 13 (92%) IPND women reporting previous pregnancy, but only 11 out of 32 (34%) IPFD women. The bleeding phenotype was assessed using the ISTH BAT score[9] with a median score of 6 for the entire cohort (normal value are \u0026lt;4 for men and \u0026lt;6 for women). There was also a difference between subgroups: a median of 3.5 in the IPND group and of 10 in the IPFD group (Table 1).\u003c/p\u003e\n\u003cp\u003eIn the entire cohort, six patients (10%) presented with associated syndromic abnormalities: three in the IPND group (15%) and three in the IPFD group (8%). The observed features included: two cases of deafness associated with nephropathy, one case of growth delay and heart disease, one case of cognitive impairment, and two cases of skeletal malformations with cognitive impairment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the IPND group, the median highest and lowest platelet counts were 108,000/mm\u0026sup3; and 56,000/mm\u0026sup3;, respectively. As expected, the IPFD group had normal or slightly reduced platelet counts, with median high and low platelet counts of 279,000/mm\u0026sup3; and 132,000/mm\u0026sup3;, respectively. The median mean platelet volume (MPV) was 11.5 fL for the entire cohort, 14.1 fL for the IPND group and 11.1 fL for the IPFD group (Table 1).\u003c/p\u003e\n\u003cp\u003ePlatelet immunophenotyping was performed in 27 patients (45%), including six patients (29%) in the IPND group and 21 patients (54%) in the IPFD group. Of the total number of patients who underwent immunophenotyping, 15 (55%) exhibited abnormal results, all of whom were in the IPFD group (patients with a Glanzmann thrombasthenia and BS diagnosis). Platelet aggregation tests were conducted in 34 cases (57%), with nine (43%) in the IPND group and 25 (64%) in the IPFD group. Seven patients (21%) had normal results and 27 (79%) had altered platelet aggregation, however, discordant results were noted in eight (30%) of the altered tests. Lastly, platelet secretion tests were performed in 16 patients (27%), with two (10%) in the IPND group and 14 (39%) in\u0026nbsp;the\u0026nbsp;IPFD\u0026nbsp;group (Table 1).\u003c/p\u003e\n\u003cp\u003eBased on the tests performed, our cohort consists of 20 patients with confirmed diagnoses (33%) and 40 with suspected diagnoses (67%) of IPDs. Among the 20 confirmed diagnoses, there is one case in the IPND group, a MYH9 macrothrombocytopenia confirmed by a genetic panel, and 19 in the IPFD group, including 13 cases of Glanzmann thrombasthenia, five cases of Bernard-Soulier syndrome and one case of storage pool disease confirmed by electron microscopy. Of the 40 suspected diagnoses, 20 patients had unspecified IPNDs and 20 had unspecified IPFDs (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e \u003cstrong\u003eList of final diagnosis of the IPD cohort\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPFD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eStorage pool disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eGlanzmann thrombasthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e13 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eBernard-Soulier syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e5 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eUnspecified inherited platelet function disorder\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e20 (33)\u003cbr\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPND\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eMYH9 macrothrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e1(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"70.12448132780084%\"\u003e\n \u003cp\u003eUnspecified inherited thrombocytopenia\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.87551867219917%\"\u003e\n \u003cp\u003e20 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend/Abbreviations: n: number; IPND: Inherited platelet number disorder; IPFD: Inherited platelet function disorders.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Inherited platelet disorders were suspected, even in the absence of diagnostic testing, when the ISTH BAT score suggested a hemorrhagic phenotype and platelet aggregation or secretion was altered.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e inherited thrombocytopeina was suspected even when diagnostic tests were not available in cases of family history, altered platelet volume, persistent long-term thrombocytopenia at stable levels, lack of response to immune thrombocytopenia treatment.\u003c/p\u003e\n\u003cp\u003eA total of 47 patients (78%) received some treatment during follow-up, including 43% of patients in the IPND group and 97% in the IPFD group. The predominant treatments included the use of antifibrinolytics (73%) and platelet transfusions (55%) prior to surgical procedures or in cases of bleeding. In the IPFD group, 90% of patients received antifibrinolytic treatment and 77% received platelet transfusions, while in the IPND group, these numbers were 43% and 14% respectively. Recombinant factor VIIa (FVIIa) was used in 8 patients, all of them with Glanzmann thrombasthenia.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eInitially described in 1948, IPDs are a rare group of diseases, with few cohorts described in the literature. Most studies show no association with sex and these diagnoses, but some indicate a higher prevalence of IPDs among women[10\u0026ndash;12]. In our cohort, there was also a predominance of women (75%). A possible explanation is the greater frequency of hemostatic challenges that women face, such as menstruation and delivery, allowing increased bleeding tendencies to be identified. \u0026nbsp;As for the distribution of ethnicity, this data is scarce in most publications. In our clinic, there was a predominance of white and mixed-race patients and a smaller proportion of black patients. However, this ethnical distribution reflects the general Brazilian population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe diagnosis of IPDs is challenging and probably most cases remain underrecognized. Misdiagnoses are also common, often resulting in inadequate treatments[13, 14]. Among patients with IPNDs, up to 30% receive an incorrect diagnosis of ITP and are sometimes treated with prolonged corticosteroid therapy, immunosuppressants, and even splenectomy[1, 15].\u003c/p\u003e\n\u003cp\u003eIn our cohort, we observed a similar occurrence, with 38% of patients in the IPND group having received prior treatment for ITP, primarily corticosteroids (38%), but also including splenectomy (10%). The IPFD group, which sometimes presents with thrombocytopenia, had a smaller proportion of patients receiving inappropriate treatments for ITP (6%), including one splenectomy (3%). When thrombocytopenia is present, it is often challenging to differentiate IPDs from ITP[13, 14]. This was represented in our cohort, as 10% of our IPD patients were earlier diagnosed with ITP. When increased bleeding occurs in the absence of thrombocytopenia, the main differential diagnosis was von Willebrand disease, with two changes in diagnosis during follow-up.\u003c/p\u003e\n\u003cp\u003eA key factor in the investigation of IPDs is a family history of thrombocytopenia or increased bleeding, which was present in more than 50% of the cohort in both subgroups. Similar data have been found in other studies evaluating IPND[13, 16], with a lack of data in IPFD cohorts. Our study reinforces the importance of having this information for diagnostic suspicion of IPD. The initial division into IPND and IPFD can also help with diagnosis, it distinguishes the primary differences between the subgroups and provides guidance for subsequent steps in the diagnostic process.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe IPFD group exhibits a severe hemorrhagic phenotype, showing a median ISTH BAT score of 10. Conversely, the IPND group showed a normal ISTH BAT score with a median of 3.5, with the caveat that we classified BS and Glanzmann thrombasthenia as IPFD.\u0026nbsp;These data are consistent with the literature, as in the ISTH BAT SCORE validation study for the IPD population the ISTH BAT SCORE results showed a median of 9 for the IPFD group and of 2 for the IPND group[17]\u003csup\u003e.\u003c/sup\u003e Comorbidities and syndromic features, although present and warranting evaluation, accounted for 10% of our sample. It is worth noting that we evaluated only adult patients, and many syndromic patients often continue to be followed by pediatric/genetic teams.\u003c/p\u003e\n\u003cp\u003eA\u003cstrong\u003es\u003c/strong\u003e for laboratory propaedeutics, the platelet counts during follow up were monitored, and thrombocytopenia was present in 25% of patients with IPFD, however it was mild and disproportionate to the hemorrhagic phenotype. For the IPND group, platelet size and morphology are important components of the diagnostic workup. In our cohort, 75% of the IPND patients had altered MPV, in line with the association of these diseases with macro platelets and giant platelets, which is helpful for diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePlatelet aggregation was carried out on patients with no suspicion of BS or Glanzmann\u0026apos;s thrombasthenia, for whom direct immunophenotyping was chosen. Thus, of the 25 remaining cases of suspected IPFD, consistently abnormal platelet aggregation confirmed the diagnosis of platelet dysfunction in 17 (44%) of them. Secretion tests were altered in seven patients, detecting only one more whose aggregation test was inconsistent, but adding little information to the other six whose diagnosis was already confirmed with the aggregation test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne limitation of our study is regarding platelet morphology, as we could not obtain this data from our cohort due to the lack of reporting standardization at our institution. Another limitation relates to platelet aggregation, which yielded 30% discordant results, making diagnostic investigation more difficult. We attribute this to pre-analytical factors, which are often described in these tests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMezanno et al. recommend the use of platelet secretion assay as a first-line investigation for IPFD but highlight the lack of standardization as a major challenge to their implementation[18]. In scenarios where resources are limited, our findings call into question the role of platelet secretion tests. When aggregation is consistent, secretion can add cost with marginal increase in diagnostic capacity. It therefore seems reasonable to focus on standardizing the platelet aggregation test and controlling pre-analytical factors. In our hospital, we do not have access to genetic mapping tools or electron microscopy; the immature platelet fraction (IPF) is still being implemented and was not used for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the available resources, we highlighted the most important points used in the investigation of IPDs and summarized them in Figure 2, as an example of a diagnostic flowchart for these conditions. Our study highlights the challenge of diagnosing IPD without genetic mapping, as two thirds of our cohorts still lacks a confirmed diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the dashed box, we have highlighted other possible tests that were not available in our institution at the time of the study. ISTH BAT: International Society on Thrombosis and Haemostasis bleeding assessment tool; ITP: immune thrombocytopenia; MPV: mean platelet volume; NGS pannel: next generation sequencing pannel; VWF: von Willebrand factor; FVIII: factor VIII; PT: prothrombin time; aPTT: partial thromboplastin time; TT: thrombin time.\u003c/p\u003e\n\u003cp\u003eFinally, regarding management, IPFD group undergo more therapeutic interventions, possibly due to a higher bleeding tendency[19], as was also observed in our cohort. Platelet transfusions and the use of antifibrinolytics were frequent in this group. On the other hand, IPNDs were treated less frequently, with transfusion triggers depending on the platelet count.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePatients with IPDs may have a higher risk of bleeding, and the vast majority will be exposed to some hemostatic challenge throughout their lives. Identifying the correct condition makes it possible to provide appropriate treatment and follow-up. In scenarios with limited resources, confirmation of the diagnosis may not always be possible. Nevertheless, the documentation of critical elements of personal and family history, the assessment of bleeding risk, and the performance of quantitative and qualitative platelet tests facilitates the identification of these patients.\u003c/p\u003e\n\u003cp\u003eOur cohort serves as an example of the management of IPDs within a public healthcare system, devoid of genetic mapping exams. Moreover, the description of this cohort sheds light on the unique characteristics of these disorders within a Latin-American population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthor contributions:\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eLDVG designed the study collected data and drafted the manuscript; EO, CR and PV revised the manuscript; FAOevaluated and discussed the results and revised the manuscript; BS designed the study and the analyses and revised the manuscript. All authors contributed to the article and approved the submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFernanda Orsi holds research grants from the National Council for Scientific and Technological Development-CNPq (grant number: 43833902018-5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Responsibilities of Authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the CEP HCFMUSP \u0026ndash;Campus S\u0026atilde;o Paulo, Brazil. Exemption from the consent form was granted due to impossibility of contact with participants and the absence of potential harms.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZaninetti C, Wolff M, Greinacher A (2021) Diagnosing Inherited Platelet Disorders: Modalities and Consequences. Hamostaseologie 41:475\u0026ndash;488\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNurden P, Stritt S, Favier R, Nurden AT (2021) Inherited platelet diseases with normal platelet count: Phenotypes, genotypes and diagnostic strategy. Haematologica 106:337\u0026ndash;350\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNurden AT, Nurden P (2020) Inherited thrombocytopenias: history, advances and perspectives. Haematologica 105:2004\u0026ndash;2019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalduini CL, Pecci A, Noris P (2012) Inherited thrombocytopenias: The evolving spectrum. Hamostaseologie 32:259\u0026ndash;270\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalma-barqueros V, Revilla N, S\u0026aacute;nchez A et al (2021) Inherited platelet disorders: An updated overview. Int J Mol Sci\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMegy K, Downes K, Simeoni I et al (2019) Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost 17:1253\u0026ndash;1260\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez Botero J, Di Paola J (2021) Diagnostic approach to the patient with a suspected inherited platelet disorder: Who and how to test. J Thromb Haemost 19:2127\u0026ndash;2136\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLambert MP (2019) Inherited Platelet Disorders: A Modern Approach to Evaluation and Treatment. Hematol Oncol Clin North Am 33:471\u0026ndash;487\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D (2010) ISTH/SSC bleeding assessment tool: A standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 8:2063\u0026ndash;2065\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026aacute;nchez-Guiu I, Ant\u0026oacute;n AI, Padilla J et al (2014) Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: Results from a collaborative study. Orphanet J Rare Dis\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBastida JM, Lozano ML, Benito R et al (2018) Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. Haematologica 103:148\u0026ndash;162\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson B, Doak R, Allsup D et al (2018) A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia. Res Pract Thromb Haemost 2:640\u0026ndash;652\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiore M, Pillois X, Lorrain S, Bernard MA, Moore N, Si\u0026eacute; P, Viallard JF, Nurden P (2016) A diagnostic approach that may help to discriminate inherited thrombocytopenia from chronic immune thrombocytopenia in adult patients. Platelets 27:555\u0026ndash;562\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold DM, Nazy I, Clare R, Jaffer AM, Aubie B, Li N, Kelton JG (2017) Misdiagnosis of primary immune thrombocytopenia and frequency of bleeding: Lessons from the McMaster ITP Registry. Blood Adv 1:2414\u0026ndash;2420\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoris P, Schlegel N, Klersy C et al (2014) Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 99:1387\u0026ndash;1394\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLassandro G, Palladino V, Faleschini M et al (2022) CHildren with Inherited Platelet disorders Surveillance (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP). Front Pediatr\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGresele P, Orsini S, Noris P et al (2020) Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC. J Thromb Haemost 18:732\u0026ndash;739\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMezzano D, Harrison P, Frelinger AL, Mumford AD, Noris P, Lordkipanidz\u0026eacute; M, Gresele P (2022) Expert opinion on the use of platelet secretion assay for the diagnosis of inherited platelet function disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology. J Thromb Haemost 20:2127\u0026ndash;2135\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrsini S, Noris P, Bury L et al (2017) Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica 102:1192\u0026ndash;1203\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"thrombocytopenia, inherited coagulation disorders, platelets, epidemiology, diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-4978578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4978578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Inherited platelet disorders (IPDs) are rare conditions characterized by altered platelet function (IPFDs) and/or reduced platelet counts (IPNDs). Diagnosing IPDs is challenging which may results in delays, misdiagnosis and unappropriated treatment. In low and middle-income countries data on these disorders are scarce. Here, we describe a cohort of IPD patients at a reference center in Brazil.\u003c/p\u003e \u003cp\u003eMethods: A descriptive analysis was conducted on patients with suspected or diagnosed IPDs at the Thrombosis and Hemostasis outpatient clinic of the Hospital das Clinicas, University of S\u0026atilde;o Paulo, Brazil. From 857 patients identified between 1998 and 2023, 60 met the eligibility criteria for suspected or confirmed IPDs. Patients with acquired causes of platelet dysfunction were excluded.\u003c/p\u003e \u003cp\u003eResults: The cohort comprised 60 patients, 65% with IPFDs and 35%, IPNDs. Women were 75%, with a median age of 48 years. IPDs were suspected based on clinical history, family history, and laboratory tests. In the IPND group, 62% had a family history of thrombocytopenia. In the IPFD group, family history was positive in 51% of cases. Previous misdiagnosis included ITP (immune thrombocytopenia) and von Willebrand disease. The bleeding phenotype, assessed using the ISTH BAT (Bleeding Assessment Tool) score, showed a median score of 6, with IPNDs scoring lower than IPFDs.\u003c/p\u003e \u003cp\u003eConclusions: Identifying IPDs is essential for proper treatment and follow-up. This study emphasizes the need for careful assessment of the familial history, bleeding risk, platelet count, morphology and function in diagnosing IPDs, particularly in low resource settings without access to advanced genetic testing.\u003c/p\u003e","manuscriptTitle":"Clinical and laboratorial characterization of a cohort of patients with hereditary platelet disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-17 13:53:32","doi":"10.21203/rs.3.rs-4978578/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec100d5e-4ece-4c32-abb2-f86e86b4d156","owner":[],"postedDate":"October 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-17T15:53:48+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-17 13:53:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4978578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4978578","identity":"rs-4978578","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}