-
Journal of Thrombosis and Haemostasis :... Nov 2012A personal history of excessive mucocutaneous bleeding is a key component in the diagnosis of a number of mild bleeding disorders, including von Willebrand disease... (Review)
Review
A personal history of excessive mucocutaneous bleeding is a key component in the diagnosis of a number of mild bleeding disorders, including von Willebrand disease (VWD), platelet function disorders (PFD), and coagulation factor deficiencies. However, the evaluation of hemorrhagic symptoms is a well-recognized challenge for both patients and physicians, because the reporting and interpretation of bleeding symptoms is subjective. As a result, bleeding assessment tools (BATs) have been developed and studied in a variety of clinical settings. This work has been pioneered by a group of Italian researchers, and the resultant 'Vicenza Bleeding Questionnaire' stands as the original BAT. In this review, we will discuss the modifications of the Vicenza Bleeding Questionnaire that have taken place over the years, as well as the validation studies that have been published. Other BATs that have been developed and published will be reviewed, as will the special situations of assessing pediatric bleeding as well as menorrhagia. Lastly, the clinical utility of BATs will be discussed including remaining challenges and future directions for the field.
Topics: Algorithms; Blood Coagulation Disorders; Blood Platelet Disorders; Female; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Humans; Male; Menorrhagia; Prevalence; Severity of Illness Index; Surveys and Questionnaires; Symptom Assessment; von Willebrand Diseases
PubMed: 22974079
DOI: 10.1111/j.1538-7836.2012.04923.x -
British Journal of Haematology Nov 2017Inherited bleeding disorders affect between 1 in 1000 individuals for the most common disorder, von Willebrand Disease, to only 8 reported cases worldwide of... (Review)
Review
Inherited bleeding disorders affect between 1 in 1000 individuals for the most common disorder, von Willebrand Disease, to only 8 reported cases worldwide of alpha-2-antiplasmin deficiency. Those with an identifiable abnormality can be divided into disorders of coagulation factors (87%), platelet count and function (8%) and the fibrinolytic system (3%). Of the patients registered in the UK with a bleeding disorder, the remaining 2% are unclassifiable. In addition to bleeding symptoms, patients with an inherited bleeding disorder can manifest other abnormalities, making an accurate and complete diagnosis that reflects the underlying molecular pathology important. Although some inherited bleeding disorders can still be easily diagnosed through a combination of careful clinical assessment and laboratory assays of varying degrees of complexity, there are many where conventional approaches are inadequate. Improvements in phenotyping assays have enhanced our diagnostic armoury but genotyping now offers the most accurate and complete diagnosis for some of these conditions. The advent of next generation sequencing technology has meant that many genes can now be analysed routinely in clinical practice. Here, we discuss the different diagnostic tools currently available for inherited bleeding disorders and suggest that genotyping should be incorporated at an early stage in the diagnostic pathway.
Topics: Abnormalities, Multiple; Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Diagnosis, Differential; Genomics; Genotype; High-Throughput Nucleotide Sequencing; Humans; Incidental Findings; Physical Examination; Platelet Function Tests; von Willebrand Diseases
PubMed: 28612396
DOI: 10.1111/bjh.14796 -
Hamostaseologie Aug 2016The sequencing of hundreds of thousands of human exomes and hundreds of thousands of whole genomes is providing a progressively accurate and complete catalogue of human... (Review)
Review
The sequencing of hundreds of thousands of human exomes and hundreds of thousands of whole genomes is providing a progressively accurate and complete catalogue of human genetic variation. The initial studies to use genome wide data to help understand platelet disorders performed genome wide association studies to identify loci linked to variations in blood cell parameters. These studies used normal variation to find corresponding genetic variation. We next wished to investigate the genetic basis of bleeding disorders which may also provide a key to novel genes regulating platelet and haemostatic functions. The BRIDGE consortium (www.bridgestudy.org) is funded by the NIHR and brings together 13 rare disease gene discovery projects. The aim of these projects is to investigate as yet undiagnosed rare inherited diseases and identify the underlying mutational basis. We have used a cluster analysis based on the Human Phenotype Ontology in combination with next generation sequencing techniques to help identify patients with similar phenotypes which we hypothesise will arise from defects in the same gene. Preliminary results validate the clustering approach and have also resulted in a number of novel genes important for normal and pathogenic platelet physiology.
Topics: Blood Platelet Disorders; Chromosome Mapping; Exome; Genetic Markers; Genetic Predisposition to Disease; Genome, Human; Hemorrhage; Humans; Polymorphism, Single Nucleotide; Prevalence
PubMed: 26781766
DOI: 10.5482/HAMO-14-11-0056 -
International Journal of Molecular... Nov 2022A single-center study was conducted on 120 patients with inherited disorders of primary hemostasis followed at our hematological center. These patients presented a...
A single-center study was conducted on 120 patients with inherited disorders of primary hemostasis followed at our hematological center. These patients presented a variety of bleeding symptoms; however, they had no definitive diagnosis. Establishing a diagnosis has consequences for the investigation of probands in families and for treatment management; therefore, we aimed to improve the diagnosis rate in these patients by implementing advanced diagnostic methods. According to the accepted international guidelines at the time of study, we investigated platelet morphology, platelet function assay, light-transmission aggregometry, and flow cytometry. Using only these methods, we were unable to make a definitive diagnosis for most of our patients. However, next-generation sequencing (NGS), which was applied in 31 patients, allowed us to establish definitive diagnoses in six cases (variants in , , and ) and helped us to identify suspected variants (, , , , , , , and and new suspected variants (, , , and ) in 11 patients. The role of NGS in patients with suspicious bleeding symptoms is growing and it changes the diagnostic algorithm. The greatest disadvantage of NGS, aside from the cost, is the occurrence of gene variants of uncertain significance.
Topics: Humans; Czech Republic; Blood Platelet Disorders; Platelet Function Tests; High-Throughput Nucleotide Sequencing; Hemorrhage; Blood Proteins
PubMed: 36430862
DOI: 10.3390/ijms232214386 -
International Journal of Molecular... Feb 2020RasGRP2 is calcium and diacylglycerol-regulated guanine nucleotide exchange factor I that activates Rap1, which is an essential signaling-knot in "inside-out" αIIbβ3... (Review)
Review
RasGRP2 is calcium and diacylglycerol-regulated guanine nucleotide exchange factor I that activates Rap1, which is an essential signaling-knot in "inside-out" αIIbβ3 integrin activation in platelets. Inherited platelet function disorder caused by variants of RASGRP2 represents a new congenital bleeding disorder referred to as platelet-type bleeding disorder-18 (BDPLT18). We review here the structure of RasGRP2 and its functions in the pathophysiology of platelets and of the other cellular types that express it. We will also examine the different pathogenic variants reported so far as well as strategies for the diagnosis and management of patients with BDPLT18.
Topics: Blood Platelet Disorders; Blood Platelets; Child, Preschool; Female; Guanine Nucleotide Exchange Factors; Hemorrhage; Humans; Infant; Male; Platelet Glycoprotein GPIIb-IIIa Complex; Shelterin Complex; Signal Transduction; Telomere-Binding Proteins
PubMed: 32041177
DOI: 10.3390/ijms21031075 -
Journal of Thrombosis and Haemostasis :... Jun 2013The majority of patients with platelet function disorders (PFDs) have normal platelet counts and mild day-to-day bleeding symptoms, but are at risk of major hemorrhage... (Review)
Review
The majority of patients with platelet function disorders (PFDs) have normal platelet counts and mild day-to-day bleeding symptoms, but are at risk of major hemorrhage at times of trauma, surgery, or childbirth. This group is challenging to investigate, because the assays are often time-intensive and labour-intensive, and interpretation is difficult, especially in patients with mild disorders. In addition, interuser variability in performance of the assays, including the currently accepted gold standard, light transmission aggregometry, makes the results difficult to compare between laboratories. Furthermore, a similar pattern of mucocutaneous bleeding is seen in disorders in other components of the hemostatic pathway, including type 1 von Willebrand disease (VWD). We have undertaken an extensive investigation of patients with clinically diagnosed excessive bleeding, using a genotyping and platelet phenotyping approach based on lumi-aggregometry, and other specialist tests of platelet function, in combination with Sanger and next-generation sequencing (NGS). We found a functional defect in ~ 60% of patients, the majority being associated with feedback pathways of platelet activation. Function-disrupting mutations were identified in known and novel genes, and coinheritance with other genetic disorders of hemostasis, including type 1 VWD, was shown. A significant number of mutations are heterozygous and unlikely to cause extensive bleeding in isolation, consistent with incomplete penetrance of inheritance of bleeding disorders and a multifactorial etiology for excessive bleeding in many patients. Mucocutaneous bleeding is a complex trait, and this has important implications for NGS in the assessment of a PFD.
Topics: Blood Platelet Disorders; Genotype; Humans; Phenotype
PubMed: 23516995
DOI: 10.1111/jth.12199 -
Transfusion Aug 2022
Review
Topics: Blood Platelet Disorders; Blood Platelets; Hemostasis; Humans; Platelet Transfusion
PubMed: 35748694
DOI: 10.1111/trf.16971 -
Hamostaseologie Oct 2022Hemostasis is a complex and tightly regulated system that attempts to maintain a homeostatic balance to permit normal blood flow, without bleeding or thrombosis.... (Review)
Review
Hemostasis is a complex and tightly regulated system that attempts to maintain a homeostatic balance to permit normal blood flow, without bleeding or thrombosis. Hemostasis reflects the subtle balance between procoagulant and anticoagulant factors in the pathways of primary hemostasis, secondary hemostasis, and fibrinolysis. The major components in this interplay include the vascular endothelium, platelets, coagulation factors, and fibrinolytic factors. After vessel wall injury, the subendothelium is exposed to the blood stream, followed by rapid activation of platelets via collagen binding and von Willebrand factor-mediated platelet adhesion to the damaged vessel wall through platelet glycoprotein receptor Ib/IX/V. Activated platelets change their shape, release bioactive molecules from their granules, and expose negatively charged phospholipids on their surface. For a proper function of this process, an adequate number of functional platelets are required. Subsequently, a rapid generation of sufficient amounts of thrombin begins; followed by activation of the coagulation system and its coagulation factors (secondary hemostasis), generating fibrin that consolidates the platelet plug. To maintain equilibrium between coagulation and anticoagulation, the naturally occurring anticoagulants such as protein C, protein S, and antithrombin keep this process in balance. Deficiencies (inherited or acquired) at any level of this fine-tuned system result in pathologic bleedings or increased hypercoagulability states leading to thrombosis. This review will focus on genetic diagnosis of inherited bleeding, thrombotic, and platelet disorders, discussing strengths and limitations of existing diagnostic settings and genetic tools and highlight some important considerations necessary for clinical application.
Topics: Humans; Protein S; von Willebrand Factor; Thrombin; Protein C; Hemostasis; Blood Platelet Disorders; Thrombosis; Blood Platelets; Blood Coagulation Factors; Hemorrhage; Fibrin; Anticoagulants; Platelet Membrane Glycoproteins; Antithrombins; Phospholipids; Collagen
PubMed: 35226963
DOI: 10.1055/a-1726-4793 -
British Medical Journal Jun 1970
Topics: Blood Platelet Disorders; Blood Platelets; Hematopoiesis; Humans; Thrombopoietin
PubMed: 5429669
DOI: 10.1136/bmj.2.5711.733-b -
Current Opinion in Hematology Sep 2021Megakaryocytes are rare hematopoietic cells that play an instrumental role in hemostasis, and other important biological processes such as immunity and wound healing.... (Review)
Review
PURPOSE OF REVIEW
Megakaryocytes are rare hematopoietic cells that play an instrumental role in hemostasis, and other important biological processes such as immunity and wound healing. With the advent of cell reprogramming technologies and advances in differentiation protocols, it is now possible to obtain megakaryocytes from any pluripotent stem cell (PSC) via hematopoietic induction. Here, we review recent advances in PSC-derived megakaryocyte (iMK) technology, focusing on platform validation, disease modeling and current limitations.
RECENT FINDINGS
A comprehensive study confirmed that iMK can recapitulate many transcriptional and functional aspects of megakaryocyte and platelet biology, including variables associated with complex genetic traits such as sex and race. These findings were corroborated by several pathological models in which iMKs revealed molecular mechanisms behind inherited platelet disorders and assessed the efficacy of novel pharmacological interventions. However, current differentiation protocols generate primarily embryonic iMK, limiting the clinical and translational potential of this system.
SUMMARY
iMK are strong candidates to model pathologic mutations involved in platelet defects and develop innovative therapeutic strategies. Future efforts on generating definitive hematopoietic progenitors would improve current platelet generation protocols and expand our capacity to model neonatal and adult megakaryocyte disorders.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Cell Differentiation; Genetic Diseases, Inborn; Hematopoiesis; Humans; Megakaryocytes; Models, Genetic; Pluripotent Stem Cells
PubMed: 34397590
DOI: 10.1097/MOH.0000000000000671