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The Journal of Clinical Investigation Dec 2005Platelets, derived from megakaryocytes, have an essential role in thrombosis and hemostasis. Over the past 10 years, a great deal of new information has been obtained... (Review)
Review
Platelets, derived from megakaryocytes, have an essential role in thrombosis and hemostasis. Over the past 10 years, a great deal of new information has been obtained concerning the various aspects of hematopoiesis necessary to maintain a steady-state platelet level to support physiologic hemostasis. Here we discuss the differentiation of HSCs into megakaryocytes, with emphasis on the key cytokine signaling pathways and hematopoietic transcription factors. Recent insight into these processes elucidates the molecular bases of numerous acquired and inherited hematologic disorders. It is anticipated that the growing knowledge in these areas may be exploited for new therapeutic strategies to modulate both platelet numbers and their thrombogenicity.
Topics: Animals; Blood Platelet Disorders; Cell Differentiation; Cell Lineage; Cytokines; Hematopoiesis; Humans; Megakaryocytes; Models, Biological; Platelet Count; Signal Transduction; Thrombopoietin; Transcription Factors
PubMed: 16322777
DOI: 10.1172/JCI26720 -
The Annals of Thoracic Surgery Jan 2009
Topics: Blood Platelet Disorders; Heart-Assist Devices; Humans; Postoperative Hemorrhage; Prognosis; von Willebrand Factor
PubMed: 19101286
DOI: 10.1016/j.athoracsur.2008.11.002 -
Journal of Thrombosis and Haemostasis :... Jul 2017Hereditary bleeding and platelet disorders (BPDs) are characterized by marked genetic heterogeneity, far greater than previously appreciated. The list of genes involved... (Review)
Review
Hereditary bleeding and platelet disorders (BPDs) are characterized by marked genetic heterogeneity, far greater than previously appreciated. The list of genes involved in the regulation of megakaryopoiesis, platelet formation, platelet function and bleeding has been growing rapidly since the introduction of high-throughput sequencing (HTS) approaches in research. Thanks to the gradual adoption of HTS in diagnostic practice, these discoveries are improving the diagnostic yield for BPD patients, who may or may not present with bleeding problems and often have other clinical symptoms unrelated to the blood system. However, it was previously found that screening for all known etiologies gives a diagnostic yield of over 90% when the phenotype closely matches a known BPD but drops to 10% when the phenotype is indicative of a novel disorder. Thus, further research is needed to identify currently unknown etiologies for BPDs. Novel genes are likely to be found to be implicated in BPDs. New modes of inheritance, including digenic inheritance, are likely to play a role in some cases. Additionally, identifying and interpreting pathogenic variants outside exons is a looming challenge that can only be tackled with an improved understanding of the regulatory landscape of relevant cell types and with the transition from targeted sequencing to whole-genome sequencing in the clinic.
Topics: Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Blood Platelets; Genetic Predisposition to Disease; Genetic Variation; Genome; Hemophilia A; Hemorrhage; High-Throughput Nucleotide Sequencing; Humans; Male; Phenotype; Sequence Analysis, DNA
PubMed: 28671349
DOI: 10.1111/jth.13681 -
Revista Espanola de Cardiologia Jul 2011The fundamental relationship between blood disorders and the cardiovascular system originates within multiple points of interface, ranging from the heart and its... (Review)
Review
The fundamental relationship between blood disorders and the cardiovascular system originates within multiple points of interface, ranging from the heart and its structural constituents to include heart chambers, valves, coronary arteries, coronary veins, and the cerebrovascular and peripheral vasculature. While the cellular components of circulating blood derive their primary origin from multipotent progenitor cells, plasma-based components, which include coagulation proteins, are mostly born of hepatic synthesis and endothelial cells. Here we provide a focused overview of nononcological blood disorders and their potential impact on the arterial circulatory system as common phenotypes, including myocardial infarction, ischemic stroke and peripheral arterial occlusive events. Venous thromboembolism is employed in our discussion as a clinical template. We also provide practical steps and guidance for diagnostic testing and management in routine clinical practice. Full English text available from: www.revespcardiol.org.
Topics: Animals; Blood Coagulation Disorders; Blood Platelet Disorders; Erythrocytes; Heart Diseases; Hematologic Diseases; Humans; Thrombophilia; Thrombosis
PubMed: 21640462
DOI: 10.1016/j.recesp.2011.02.018 -
The Journal of Clinical Investigation Dec 2005Our understanding of thrombopoiesis--the formation of blood platelets--has improved greatly in the last decade, with the cloning and characterization of thrombopoietin,... (Review)
Review
Our understanding of thrombopoiesis--the formation of blood platelets--has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Cell Differentiation; Gene Expression Regulation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Ligands; Models, Biological; Models, Molecular; Protein Structure, Tertiary; Proto-Oncogene Proteins; Receptors, Cytokine; Receptors, Thrombopoietin; Signal Transduction; Thrombopoiesis; Thrombopoietin; Wound Healing
PubMed: 16322778
DOI: 10.1172/JCI26674 -
British Journal of Haematology Apr 2009Unexpectedly high rates of venous thromboembolic events (VTE) concurrent with the introduction of highly effective immune modulating drugs thalidomide and lenolidomide... (Review)
Review
Unexpectedly high rates of venous thromboembolic events (VTE) concurrent with the introduction of highly effective immune modulating drugs thalidomide and lenolidomide for treatment of multiple myeloma have focused attention on the incidence and underlying pathophysiology of VTE in patients with plasma cell dyscrasias, and on thromboprophylaxis approaches. While bleeding complications are relatively uncommon in patients with lymphoproliferative disorders, acquired von Willebrand syndrome, typically occurring in patients with monoclonal gammopathy of unknown significance, and acquired coagulopathies associated with primary amyloidosis can present with haemorrhagic complications and both are challenging to manage. This review highlights these important haemostasis-related complications of plasma cell dyscrasias and provides an overview of other uncommon bleeding and thrombotic events that can affect diagnostic and therapeutic management of clonal plasma cell disorders. Due to the infrequency of most of these haemostasis complications, available information is typically based on retrospective cases or series.
Topics: Blood Coagulation Disorders; Blood Platelet Disorders; Boronic Acids; Bortezomib; Hemorrhage; Humans; Immunosuppressive Agents; Paraproteinemias; Protease Inhibitors; Pyrazines; Retrospective Studies; Thalidomide; Thrombosis
PubMed: 19210509
DOI: 10.1111/j.1365-2141.2008.07577.x -
Scientific Reports Aug 2021To reveal if coagulopathies relate to the course of COVID-19, we examined 255 patients with moderate and severe COVID-19, receiving anticoagulants and immunosuppressive...
To reveal if coagulopathies relate to the course of COVID-19, we examined 255 patients with moderate and severe COVID-19, receiving anticoagulants and immunosuppressive drugs. Coagulopathy manifested predominantly as hypercoagulability that correlated directly with systemic inflammation, disease severity, comorbidities, and mortality risk. The prolonged clotting tests in about ¼ of cases were associated with high levels of C-reactive protein and antiphospholipid antibodies, which impeded coagulation in vitro. Contraction of blood clots was hindered in about ½ of patients, especially in severe and fatal cases, and correlated directly with prothrombotic parameters. A decrease in platelet contractility was due to moderate thrombocytopenia in combination with platelet dysfunction. Clots with impaired contraction were porous, had a low content of compressed polyhedral erythrocytes (polyhedrocytes) and an even distribution of fibrin, suggesting that the uncompacted intravital clots are more obstructive but patients could also be prone to bleeding. The absence of consumption coagulopathy suggests the predominance of local and/or regional microthrombosis rather than disseminated intravascular coagulation. The results obtained (i) confirm the importance of hemostatic disorders in COVID-19 and their relation to systemic inflammation; (ii) justify monitoring of hemostasis, including the kinetics of blood clot contraction; (iii) substantiate the active prophylaxis of thrombotic complications in COVID-19.
Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; COVID-19; Female; Humans; Inflammation; Male; Middle Aged; Patient Acuity; Thrombocytopenia; Treatment Outcome; Young Adult; COVID-19 Drug Treatment
PubMed: 34381066
DOI: 10.1038/s41598-021-95397-6 -
The Journal of Surgical Research Feb 2020Platelet function tests such as thrombelastography platelet mapping and impedance aggregometry have demonstrated universal platelet dysfunction in trauma patients. In... (Observational Study)
Observational Study
BACKGROUND
Platelet function tests such as thrombelastography platelet mapping and impedance aggregometry have demonstrated universal platelet dysfunction in trauma patients. In this study, we introduce the measurement of platelet contraction force as a test of platelet function. We hypothesize that force will correlate with established coagulation tests such as thrombelastography, demonstrate significant differences between healthy subjects and trauma patients, and identify critically ill trauma patients.
METHODS
Blood samples were prospectively collected from level 1 trauma patients at initial presentation, assayed for force of and time to contraction and compared with thrombelastography. Blood from healthy subjects was assayed to establish a reference range. Results from trauma patients were compared with healthy controls and trauma patients that died.
RESULTS
The study includes one hundred trauma patients with mean age 45 y, 74% were male, and median injury severity score of 14 ± 12. Patients that survived (n = 90) demonstrated significantly elevated platelet contraction force compared with healthy controls (n = 12) (6390 ± 2340 versus 4790 ± 470 μN, P = 0.043) and trauma patients that died (n = 10) (6390 ± 2340 versus 2860 ± 1830 μN, P = 0.0001). Elapsed time to start of platelet contraction was faster in trauma patients that survived compared with healthy controls (660 ± 467 versus 1130 ± 140 s, P = 0.0022) and those that died (660 ± 470 versus 1460 ± 1340 s, P < 0.0001).
CONCLUSIONS
In contrast with all existing platelet function tests reported in the literature, which report platelet dysfunction in trauma patients, contractile force demonstrates hyperfunction in surviving trauma patients and dysfunction in nonsurvivors. Platelet contraction reflects platelet metabolic reserve and thus may be a potential biomarker for survival after trauma. Contractile force warrants further investigation to predict mortality in severely injured trauma patients.
Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation; Blood Platelet Disorders; Blood Platelets; Female; Humans; Injury Severity Score; Male; Middle Aged; Platelet Function Tests; Predictive Value of Tests; Prognosis; Prospective Studies; ROC Curve; Thrombelastography; Wounds and Injuries; Young Adult
PubMed: 31668435
DOI: 10.1016/j.jss.2019.09.052 -
International Journal of Laboratory... Dec 2021Studies of thrombin generation (TG) with platelet-rich plasma (PRP) and platelet-poor plasma (PPP) have provided insights on bleeding disorders. We studied TG for a...
INTRODUCTION
Studies of thrombin generation (TG) with platelet-rich plasma (PRP) and platelet-poor plasma (PPP) have provided insights on bleeding disorders. We studied TG for a cohort with commonly encountered platelet function disorders (PFD).
METHODS
Participants included 40 controls and 31 with PFD due to: nonsyndromic dense granule (DG) deficiency (PFD-DGD, n = 9), RUNX1 haploinsufficiency (n = 6) and aggregation defects from other, uncharacterized causes (n = 16). TG was tested with PRP and PPP samples. As DG store ADP and polyphosphate that enhance platelet-dependent TG, PFD-DGD PRP TG was tested for correction with ADP, polyphosphate and combined additives. Tissue factor pathway inhibitor (TFPI), platelet factor V (FV), and platelet TFPI and ANO6 transcript levels were also evaluated. Findings were tested for associations with TG endpoints and bleeding.
RESULTS
PFD samples had impaired PRP TG, but also impaired PPP TG, with strong associations between their PRP and PPP TG endpoints (P ≤ .005). PFD-DGD PRP TG endpoints showed associations to PPP TG endpoints but not to DG counts, and were improved, but not fully corrected, by adding polyphosphate and agonists. PFD participants had increased plasma TFPI and reduced platelet TFPI (P ≤ .02) but normal levels of platelet FV, and platelet TFPI and ANO6 transcripts levels. PFD plasma TFPI levels showed significant association to several PPP TG endpoints (P ≤ .04). Several PFD PRP TG endpoints showed significant associations to bleeding symptoms, including wound healing problems and prolonged bleeding from minor cuts (P ≤ .04).
CONCLUSION
TG is impaired in commonly encountered PFD, with their PRP TG findings showing interesting associations to symptoms.
Topics: Biomarkers; Blood Coagulation; Blood Coagulation Tests; Blood Platelet Disorders; Disease Management; Disease Susceptibility; Humans; Phenotype; Platelet-Rich Plasma; Prognosis; Thrombin
PubMed: 34185390
DOI: 10.1111/ijlh.13638 -
British Journal of Haematology Apr 2014Genetic defects of platelets constitute rare diseases that include bleeding syndromes of autosomal dominant, recessive or X-linked inheritance. They affect platelet... (Review)
Review
Genetic defects of platelets constitute rare diseases that include bleeding syndromes of autosomal dominant, recessive or X-linked inheritance. They affect platelet production, resulting in a low circulating platelet count and changes in platelet morphology, platelet function, or a combination of both with altered megakaryopoiesis and a defective platelet response. As a result, blood platelets fail to fulfil their haemostatic function. Most studied of the platelet function disorders are deficiencies of glycoprotein mediators of adhesion and aggregation while defects of primary receptors for stimuli include the P2Y12 ADP receptor. Studies on inherited defects of (i) secretion from storage organelles (dense granules, α-granules), (ii) the platelet cytoskeleton and (iii) the generation of pro-coagulant activity have identified genes indirectly controlling the functional response. Signalling pathway defects leading to agonist-specific modifications of platelet aggregation are the current target of exome-sequencing strategies. We now review recent advances in the molecular characterization of platelet function defects.
Topics: Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Blood Platelets; Humans; Platelet Adhesiveness; Purpura, Thrombotic Thrombocytopenic; Receptors, Cell Surface; Signal Transduction; Thrombasthenia
PubMed: 24286193
DOI: 10.1111/bjh.12662