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Blood Dec 2019A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes,...
A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
Topics: Blood Platelet Disorders; Female; Gene Dosage; Hemorrhage; Hemostasis; High-Throughput Nucleotide Sequencing; Humans; Male; Thrombosis
PubMed: 31064749
DOI: 10.1182/blood.2018891192 -
Blood Apr 2023Within the first months of the COVID-19 vaccination campaign, previously healthy recipients who developed severe thrombosis (often cerebral and/or splanchnic...
Within the first months of the COVID-19 vaccination campaign, previously healthy recipients who developed severe thrombosis (often cerebral and/or splanchnic vasculature) and thrombocytopenia typically after adenoviral vector-based vaccination were identified. Similarities between this syndrome, vaccine-induced immune thrombotic thrombocytopenia (VITT), and heparin-induced thrombocytopenia prompted recognition of the role of antiplatelet factor 4 (PF4) antibodies and management strategies based on IV immunoglobulin and nonheparin anticoagulants, which improved outcome. We update current understanding of VITT and potential involvement of anti-PF4 antibodies in thrombotic disorders.
Topics: Humans; COVID-19 Vaccines; COVID-19; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombosis; Vaccines; Platelet Factor 4
PubMed: 36669155
DOI: 10.1182/blood.2022017696 -
International Journal of Molecular... Apr 2021Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 10 platelet per day as... (Review)
Review
Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 10 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype-phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.
Topics: Blood Platelet Disorders; Blood Platelets; Genetic Testing; Hemostasis; High-Throughput Nucleotide Sequencing; Humans; Platelet Function Tests; Platelet Transfusion; Rare Diseases
PubMed: 33926054
DOI: 10.3390/ijms22094521 -
Journal of Thrombosis and Haemostasis :... Aug 2016Mild inherited bleeding disorders are relatively common in the general population. Despite recent advances in diagnostic approaches, mild inherited bleeding disorders... (Review)
Review
Mild inherited bleeding disorders are relatively common in the general population. Despite recent advances in diagnostic approaches, mild inherited bleeding disorders still pose a significant diagnostic challenge. Hemorrhagic diathesis can be caused by disorders in primary hemostasis (von Willebrand disease, inherited platelet function disorders), secondary hemostasis (hemophilia A and B, other (rare) coagulant factor deficiencies) and fibrinolysis, and in connective tissue or vascular formation. This review summarizes the currently available diagnostic methods for mild bleeding disorders and their pitfalls, from structured patient history to highly specialized laboratory diagnosis. A comprehensive framework for a diagnostic approach to mild inherited bleeding disorders is proposed.
Topics: Blood Coagulation; Blood Platelet Disorders; Blood Platelets; Coagulants; Fibrinolysis; Genetic Testing; Hematology; Hemophilia A; Hemophilia B; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Humans; Mutation; von Willebrand Diseases
PubMed: 27208505
DOI: 10.1111/jth.13368 -
Obstetrics and Gynecology Mar 2019Obstetricians frequently diagnose thrombocytopenia in pregnant women because platelet counts are included with automated complete blood cell counts obtained during...
Obstetricians frequently diagnose thrombocytopenia in pregnant women because platelet counts are included with automated complete blood cell counts obtained during routine prenatal screening (). Although most U.S. health care providers are trained using U.S. Conventional Units, most scientists, journals, and countries use Système International (SI) units. The laboratory results reported in U.S. Conventional Units can be converted to SI Units or vice versa by using a conversion factor. Given the conversion factor is 1.0, when converting from 10/μL to 10/L the platelet "count" does not seemingly change. Thrombocytopenia, defined as a platelet count of less than 150 × 10/L, is common and occurs in 7-12% of pregnancies at the time of delivery (). Thrombocytopenia can result from a variety of physiologic or pathologic conditions, several of which are unique to pregnancy. Some causes of thrombocytopenia are serious medical disorders that have the potential for maternal and fetal morbidity. In contrast, other conditions, such as gestational thrombocytopenia, are benign and pose no maternal or fetal risks. Because of the increased recognition of maternal and fetal thrombocytopenia, there are numerous controversies about obstetric management of this condition. Clinicians must weigh the risks of maternal and fetal bleeding complications against the costs and morbidity of diagnostic tests and invasive interventions. This Practice Bulletin is a targeted revision to reflect limited changes to information about new estimates for thrombocytopenia in pregnancy and the risk of recurrence of fetal-neonatal alloimmune thrombocytopenia in subsequent pregnancies, and to provide new information on the level of thrombocytopenia that permits regional anesthesia.
Topics: Female; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia
PubMed: 30801473
DOI: 10.1097/AOG.0000000000003100 -
Pediatrics in Review May 2020After vascular injury and exposure of subendothelial matrix proteins to the intravascular space, mediators of hemostasis are triggered and allow for clot formation and... (Review)
Review
After vascular injury and exposure of subendothelial matrix proteins to the intravascular space, mediators of hemostasis are triggered and allow for clot formation and restoration of vascular integrity. Platelets are the mediators of primary hemostasis, creating a platelet plug and allowing for initial cessation of bleeding. Platelet disorders, qualitative and quantitative, may result in bleeding signs and symptoms, particularly mucocutaneous bleeding such as epistaxis, bruising, petechiae, and heavy menstrual bleeding. Increasing evidence suggests that platelets have functional capabilities beyond hemostasis, but this review focuses solely on platelet hemostatic properties. Herein, normal platelet function as well as the effects of abnormal function and thrombocytopenia are reviewed.
Topics: Blood Platelet Disorders; Child; Diagnosis, Differential; Humans; Pediatrics; Referral and Consultation
PubMed: 32358028
DOI: 10.1542/pir.2018-0359 -
Nature Reviews. Cardiology Mar 2021The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in... (Review)
Review
The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
Topics: Administration, Inhalation; Anticoagulants; Blood Coagulation Disorders; Blood Platelet Disorders; COVID-19; Endothelium, Vascular; Endothelium-Dependent Relaxing Factors; Epoprostenol; Heart Disease Risk Factors; Humans; Iloprost; Inflammation; Nitric Oxide; Platelet Aggregation Inhibitors; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Thrombosis; Thrombotic Microangiopathies; Vascular Diseases; Vasodilator Agents; Venous Thromboembolism; COVID-19 Drug Treatment
PubMed: 33214651
DOI: 10.1038/s41569-020-00469-1 -
Blood Aug 2022Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia in children and is caused by immune-mediated decreased platelet production and increased...
Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia in children and is caused by immune-mediated decreased platelet production and increased platelet destruction. In the absence of a diagnostic test, ITP must be differentiated from other thrombocytopenic disorders, including inherited platelet disorders. In addition, a diagnosis of secondary ITP due to a primary immune deficiency with immune dysregulation may not be apparent at diagnosis but can alter management and should be considered in an expanding number of clinical scenarios. The diagnostic evaluation of children with thrombocytopenia will vary based on the clinical history and laboratory features. Access to genotyping has broadened the ability to specify the etiology of thrombocytopenia, whereas increasing access to immunophenotyping, functional immunologic and platelet assays, and biochemical markers has allowed for more in-depth evaluation of patients. With this greater availability of testing, diagnostic algorithms in patients with thrombocytopenia have become complex. In this article, we highlight the diagnostic evaluation of thrombocytopenia in children with a focus on ITP, including consideration of underlying genetic and immune disorders, and use hypothetical patient cases to describe disease manifestations and strategies for treatment of pediatric ITP.
Topics: Biomarkers; Blood Platelets; Child; Humans; Leukopenia; Neuroblastoma; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia
PubMed: 34479363
DOI: 10.1182/blood.2020006480 -
Hematology/oncology Clinics of North... Dec 2021
Topics: Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Humans
PubMed: 34620520
DOI: 10.1016/j.hoc.2021.09.001 -
Platelets Sep 2016
Topics: Blood Platelet Disorders; Blood Platelets; Humans; Research
PubMed: 27540958
DOI: 10.1080/09537104.2016.1213058