Inherited Platelet Disorders: an Updated Overview
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Protein S Deficiency Presenting with Hemorrhage in a Term Neonate
: Curre re nt a R C e Ayari et al., Health Care Current Reviews 2018, 6:1 h v t i l e a w DOI: 10.4172/2375-4273.1000219 e s H Health Care: Current Reviews ISSN: 2375-4273 Review Article Open Access Protein S Deficiency Presenting with Hemorrhage in a Term Neonate Fairouz Ayari*, Takoua Bensmail, Essid Latifa, Wiem Barbaria and Samia Kacem Neonatology Intensive Care Unit of the Maternity and Neonatology Center, Tunis, Tunisia Abstract Unexplained bleeding symptoms in otherwise healthy full-term usually present a diagnostic challenge for treating physicians requiring prompt and accurate laboratory investigations to ensure appropriate treatment and possibly avoid long-term morbidity. We report a case of a term neonate with severe protein S deficiency manifested by systemic hemorrhage and multiple organ failure at 9 days of age. We review how protein S influences the coagulation and the fibrinolytic pathways, discussing therapeutic approaches of neonates with purpura fulminans. Keywords: Protein S deficiency; Blood sample; Thrombophilic dis- resuscitation with 20 ml/kg bodyweight (BW) saline solution and, after order blood sampling, intravenous administration of 10 mg vitamin K, 20 ml/kg BW fresh frozen plasma, 20 ml/kg BW packed red blood cells Introduction (5 transfusion cycles), 20 mg/kg BW Phenobarbital and vasoactive Protein S (PS) is an antithrombotic plasma protein that acts mainly drugs. Cerebral ultrasound revealed intraventricular haemorrhage, as a cofactor of activated protein C (APC) anticoagulant activity in the abdominal ultrasound showed splenic hemorrhage and cardiac degradation of factor Va and activated factor VIII [1]. PS circulates in ultrasound showed a floating intracardiac thrombus. -
Diagnosing Platelet Secretion Disorders: Examples Cases
Diagnosing platelet secretion disorders: examples cases Martina Daly Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Disclosures for Martina Daly In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board Platelet granule release Agonists (FIIa, Collagen, ADP) Signals Activation Shape change Membrane fusion Release of granule contents Platelet storage organelles lysosomes a granules Enzymes including cathepsins Adhesive proteins acid hydrolases Clotting factors and their inhibitors Fibrinolytic factors and their inhibitors Proteases and antiproteases Growth and mitogenic factors Chemokines, cytokines Anti-microbial proteins Membrane glycoproteins dense (d) granules ADP/ATP Serotonin histamine inorganic polyphosphate Platelet a-granule contents Type Prominent components Membrane glycoproteins GPIb, aIIbb3, GPVI Clotting factors VWF, FV, FXI, FII, Fibrinogen, HMWK, FXIII? Clotting inhibitors TFPI, protein S, protease nexin-2 Fibrinolysis components PAI-1, TAFI, a2-antiplasmin, plasminogen, uPA Other protease inhibitors a1-antitrypsin, a2-macroglobulin -
Distinct but Critical Roles for Integrin Aiibb3 in Platelet Lamellipodia Formation on Fibrinogen, Collagen-Related Peptide and T
Distinct but critical roles for integrin aIIbb3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin Kelly Thornber1, Owen J. T. McCarty2,3, Steve P. Watson2 and Catherine J. Pears1 1 Department of Biochemistry, University of Oxford, UK 2 Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, UK 3 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA Keywords Integrins are the major receptor type known to facilitate cell adhesion and aIIbb3; adhesion; integrins; lamellipodia; lamellipodia formation on extracellular matrix proteins. However, collagen- platelets related peptide and thrombin have recently been shown to mediate platelet lamellipodia formation when presented as immobilized surfaces. The aims Correspondence C. Pears, Department of Biochemistry, of this study were to establish if there exists a role for the platelet integrin South Parks Road, University of Oxford, aIIbb3 in this response; and if so, whether signalling from the integrin is Oxford, OX1 3QU, UK required for lamellipodia formation on these surfaces. Real-time analysis Fax: +44 1865 275259 was used to compare platelet morphological changes on surfaces of fibrino- Tel: +44 1865 275737 gen, collagen-related peptide or thrombin in the presence of various E-mail: [email protected] pharmacological inhibitors and platelets from ‘knockout’ mice. We demon- Website: http://www.bioch.ox.ac.uk strate that collagen-related peptide and thrombin stimulate distinct patterns 2+ (Received 11 July 2006, revised 22 August of platelet lamellipodia formation and elevation of intracellular Ca to 2006, accepted 12 September 2006) that induced by the integrin aIIbb3 ligand, fibrinogen. -
MYH9-Related Platelet Disorders
Reprinted with permission from Thieme Medical Publishers (Semin Thromb Hemost 2009;35:189-203) Homepage at www.thieme.com MYH9-Related Platelet Disorders Karina Althaus, M.D.,1 and Andreas Greinacher, M.D.1 ABSTRACT Myosin heavy chain 9 (MYH9)-related platelet disorders belong to the group of inherited thrombocytopenias. The MYH9 gene encodes the nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cytoskeletal contractile protein. Several mutations in the MYH9 gene lead to premature release of platelets from the bone marrow, macro- thrombocytopenia, and cytoplasmic inclusion bodies within leukocytes. Four overlapping syndromes, known as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian platelet syndrome, describe different clinical manifestations of MYH9 gene mutations. Macrothrombocytopenia is present in all affected individuals, whereas only some develop additional clinical manifestations such as renal failure, hearing loss, and presenile cataracts. The bleeding tendency is usually moderate, with menorrhagia and easy bruising being most frequent. The biggest risk for the individual is inappropriate treatment due to misdiagnosis of chronic autoimmune thrombocytopenia. To date, 31 mutations of the MYH9 gene leading to macrothrombocytopenia have been identified, of which the upstream mutations up to amino acid 1400 are more likely associated with syndromic manifestations than the downstream mutations. This review provides a short history of MYH9-related disorders, summarizes the clinical and laboratory character- istics, describes a diagnostic algorithm, presents recent results of animal models, and discusses aspects of therapeutic management. KEYWORDS: MYH9 gene, nonmuscle myosin IIA, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Sebastian platelet syndrome, macrothrombocytopenia The correct diagnosis of hereditary chronic as isolated platelet count reductions or as part of thrombocytopenias is important for planning appropri- more complex clinical syndromes. -
Alterations in Platelet Alpha-Granule Secretion and Adhesion on Collagen Under Flow in Mice Lacking the Atypical Rho Gtpase Rhobtb3
cells Article Alterations in Platelet Alpha-Granule Secretion and Adhesion on Collagen under Flow in Mice Lacking the Atypical Rho GTPase RhoBTB3 Martin Berger 1,2, David R. J. Riley 1, Julia Lutz 1, Jawad S. Khalil 1, Ahmed Aburima 1, Khalid M. Naseem 3 and Francisco Rivero 1,* 1 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, HU6 7RX Hull, UK; [email protected] (M.B.); [email protected] (D.R.J.R.); [email protected] (J.L.); [email protected] (J.S.K.); [email protected] (A.A.) 2 Department of Internal Medicine 1, University Hospital, RWTH Aachen, 52074 Aachen, Germany 3 Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, LS2 9NL Leeds, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-1482-466433 Received: 8 January 2019; Accepted: 7 February 2019; Published: 11 February 2019 Abstract: Typical Rho GTPases, such as Rac1, Cdc42, and RhoA, act as molecular switches regulating various aspects of platelet cytoskeleton reorganization. The loss of these enzymes results in reduced platelet functionality. Atypical Rho GTPases of the RhoBTB subfamily are characterized by divergent domain architecture. One family member, RhoBTB3, is expressed in platelets, but its function is unclear. In the present study we examined the role of RhoBTB3 in platelet function using a knockout mouse model. We found the platelet count, size, numbers of both alpha and dense granules, and surface receptor profile in these mice were comparable to wild-type mice. -
Thrombocytopenia-Absent Radius Syndrome
Thrombocytopenia-absent radius syndrome Description Thrombocytopenia-absent radius (TAR) syndrome is characterized by the absence of a bone called the radius in each forearm and a shortage (deficiency) of blood cells involved in clotting (platelets). This platelet deficiency (thrombocytopenia) usually appears during infancy and becomes less severe over time; in some cases the platelet levels become normal. Thrombocytopenia prevents normal blood clotting, resulting in easy bruising and frequent nosebleeds. Potentially life-threatening episodes of severe bleeding ( hemorrhages) may occur in the brain and other organs, especially during the first year of life. Hemorrhages can damage the brain and lead to intellectual disability. Affected children who survive this period and do not have damaging hemorrhages in the brain usually have a normal life expectancy and normal intellectual development. The severity of skeletal problems in TAR syndrome varies among affected individuals. The radius, which is the bone on the thumb side of the forearm, is almost always missing in both arms. The other bone in the forearm, which is called the ulna, is sometimes underdeveloped or absent in one or both arms. TAR syndrome is unusual among similar malformations in that affected individuals have thumbs, while people with other conditions involving an absent radius typically do not. However, there may be other abnormalities of the hands, such as webbed or fused fingers (syndactyly) or curved pinky fingers (fifth finger clinodactyly). Some people with TAR syndrome also have skeletal abnormalities affecting the upper arms, legs, or hip sockets. Other features that can occur in TAR syndrome include malformations of the heart or kidneys. -
Hemoglobin Interaction with Gp1ba Induces Platelet Activation And
ARTICLE Platelet Biology & its Disorders Hemoglobin interaction with GP1bα induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis Rashi Singhal,1,2,* Gowtham K. Annarapu,1,2,* Ankita Pandey,1 Sheetal Chawla,1 Amrita Ojha,1 Avinash Gupta,1 Miguel A. Cruz,3 Tulika Seth4 and Prasenjit Guchhait1 1Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India; 2Biotechnology Department, Manipal University, Manipal, Karnataka, India; 3Thrombosis Research Division, Baylor College of Medicine, Houston, TX, USA, and 4Hematology, All India Institute of Medical Sciences, New Delhi, India *RS and GKA contributed equally to this work. ABSTRACT Intravascular hemolysis increases the risk of hypercoagulation and thrombosis in hemolytic disorders. Our study shows a novel mechanism by which extracellular hemoglobin directly affects platelet activation. The binding of Hb to glycoprotein1bα activates platelets. Lower concentrations of Hb (0.37-3 mM) significantly increase the phos- phorylation of signaling adapter proteins, such as Lyn, PI3K, AKT, and ERK, and promote platelet aggregation in vitro. Higher concentrations of Hb (3-6 mM) activate the pro-apoptotic proteins Bak, Bax, cytochrome c, caspase-9 and caspase-3, and increase platelet clot formation. Increased plasma Hb activates platelets and promotes their apoptosis, and plays a crucial role in the pathogenesis of aggregation and development of the procoagulant state in hemolytic disorders. Furthermore, we show that in patients with paroxysmal nocturnal hemoglobinuria, a chronic hemolytic disease characterized by recurrent events of intravascular thrombosis and thromboembolism, it is the elevated plasma Hb or platelet surface bound Hb that positively correlates with platelet activation. -
Nihms124287.Pdf (2.042Mb)
Intragranular Vesiculotubular Compartments are Involved in Piecemeal Degranulation by Activated Human Eosinophils The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Melo, Rossana C.N., Sandra A.C. Perez, Lisa A. Spencer, Ann M. Dvorak, and Peter F. Weller. 2005. “Intragranular Vesiculotubular Compartments Are Involved in Piecemeal Degranulation by Activated Human Eosinophils.” Traffic 6 (10) (July 28): 866–879. doi:10.1111/j.1600-0854.2005.00322.x. Published Version doi:10.1111/j.1600-0854.2005.00322.x Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:28714144 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Traffic. Author manuscript; available in PMC 2009 July 24. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Traffic. 2005 October ; 6(10): 866±879. doi:10.1111/j.1600-0854.2005.00322.x. Intragranular Vesiculotubular Compartments are Involved in Piecemeal Degranulation by Activated Human Eosinophils Rossana C.N. Melo1,2, Sandra A.C. Perez2, Lisa A. Spencer2, Ann M. Dvorak3, and Peter F. Weller2,* 1Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, UFJF, Juiz de Fora, MG, Brazil 2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 3Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Abstract Eosinophils, leukocytes involved in allergic, inflammatory and immunoregulatory responses, have a distinct capacity to rapidly secrete preformed granule-stored proteins through piecemeal degranulation (PMD), a secretion process based on vesicular transport of proteins from within granules for extracellular release. -
Homozygous Delta-Beta Thalassemia in a Child: a Rare Cause of Elevated Fetal Hemoglobin
Case Report Homozygous delta-beta Thalassemia in a Child: a Rare Cause of Elevated Fetal Hemoglobin Verma S MD1, Bhargava M MD2, Mittal SK MD 3, Gupta R MD4 1. Senior Resident, Department of Pathology, Chacha Nehru Bal Chikitsalaya, Delhi,India. 2. Consultant Pathologist, Department of Pathology, Pushpanjali Crosslay Hospital,India. 3. Director & Senior Consultant, Department of Pediatrics, Pushpanjali Crosslay Hospital,India. 4. Assistant Professor and Head, Departments of Pathology, Chacha Nehru Bal Chikitsalaya, Delhi,India. Received: 15 November 2012 Accepted: 26 January 2013 Abstract Background complete absence of HbA and HbA2 with HbF Delta beta (δβ) thalassemia is an unusual variant of constituting 100% of the hemoglobin. Hemoglobin thalassemia with elevated level of fetal hemoglobin analysis of both parents showed elevated level of (HbF). Homozygous patients of this disorder, unlike HbF with normal HbA2. A final diagnosis of δβ- β-thalassemia, show mild anemia. Only few cases of thalassemia in the child with both parents being δβ-thalassemia have been reported from India in the carriers was rendered. available indexed English literature. Conclusion Case presentation Delta beta-thalassemia is an uncommon cause of A four-year old male child was evaluated for recent- markedly elevated fetal hemoglobin beyond fetal onset jaundice. Hematological investigations showed period. Clinical and haematological parameters mild anemia with microcytic hypochromic red cells. should be evaluated to render an accurate diagnosis. A comprehensive analysis of hemoglobin by high- Key Words performance liquid chromatography (HPLC) showed Delta-Beta Thalassemia ;Homozygote; Chromatography, High Pressure Liquid Corresponding Author Ruchika Gupta,Department of Pathology,Chacha Nehru Bal Chikitsalaya (Associate Hospital of Maulana Azad Medical College),Geeta Colony,Delhi (India), E-mail: [email protected] Introduction confirmatory test for diagnosis of this rare disorder Delta beta (δβ) thalassemia is an infrequent cause of (4). -
Graft Versus Host Disease and How to Report It
Graft versus Host Disease and how to report it Daniel Weisdorf MD University of Minnesota Transplant Events Day-8 0 1mo 3mo 6mo Conditioning HSCT Engraftment Mucositis Organ toxicity (VOD) Acute GVHD Chronic GVHD Infections Bacterial ----CMV---- Varicella----- --Fungus--------- Transplant Events Day-8 0 1mo 3mo 6mo Conditioning HSCT Engraftment Mucositis Organ toxicity (VOD) Acute GVHD Chronic GVHD Infections Bacterial ----CMV---- Varicella----- --Fungus--------- 1 Acute GVHD Chronic GVHD Skin: Lichen planus, Hyper/ hypo pigmentation, Dermatitis ichthyosis, onychodystrophy, morphea, + scleroderma, hair changes. Hepatitis Oral: sicca, atrophy, lichenoid, + Hyperkeratosis GI: wasting, dysphagia, Enteritis odynophagia, strictures Eye: keratoconjunctivitis sicca Lungs: Bronchiolitis obliterans Others: myofascial, genital Acute GVHD Chronic GVHD Dermatitis Rash + Hepatitis High bilirubin + Enteritis Nausea/vomiting/ diarrhea Acute GVHD Chronic GVHD Skin: Lichen planus, Scaly abnormal pigmentation, Dry skin, onychodystrophy, abnormal nails scleroderma, thick skin hair changes. Oral: sicca, atrophy, lichenoid, Dry mouth GI: wasting, dysphagia, Weight loss odynophagia, trouble swallowing Eye: keratoconjunctivitis sicca Dry eyes Lungs: Bronchiolitis obliterans Obstruction Others: myofascial, muscle stiffness Genital vaginal narrowing 2 Graft vs. Leukemia Effect • Less leukemia relapse follows more GVHD • Acute and particularly Chronic GVHD limit relapse Risk Factors for GVHD Acute GVHD Chronic GVHD Increased risk Increased risk HLA mismatch Older -
COVID-19 and RARE SKIN DISEASES
COVID-19 and RARE SKIN DISEASES Newsletter n°4, 8th June 2021 Dear all, We hope that this letter finds you well! Thank you to those who have included patients and collected the data! We would like to remind you to complete the online eCRF via the link you have received. If you any have any issues don’t hesitate to contact us. Please note that, since the pandemic is still continuing, the study has been expanded for one year. The monitoring is ongoing and the queries will be sent regularly. If needed, the sites will be contacted to discuss and validate the answers, and check if the study is proceeding well. 64 patients are included in the study: 5 in Germany, 6 in Czech Republic, 8 in Italy, 11 in Lithuania and 34 in France. The diseases concerned are the following: Bullous pemphigoid (9/64), Recessive dystrophic Epidermolysis bullosa (9/64), Dominant dystrophic Epidermolysis bullosa (8/64), Epidermolysis bullosa (7/64), Hidradenitis suppurativa (7/64), X-linked hypohidrotic ectodermal dysplasia (4/64), Lamellar ichtyosis (2/64) and Incontinentia pigmenti (2/64). The other diseases are presented each by 1 patient: Pemphigus vulgaris, Pemphigus foliaceous, Mucous membrane pemphigoid, IgA Linear Dermatosis, Dermatitis herpetiformis, Kindler Epidermolysis bullosa, Kerathinopathic ichthyosis, Darier disease, Linear morphea, Cloves syndrome, Microcystic lymphatic malformation, Hemihypertrophy (Overgrowth syndrome), Adamantiades - Behçet's disease, Hailey Hailey disease, Pityriasis rubra pilaris and Neurofibromatosis type 1 (Figure 1 below). 10 Figure 1: Type of Rare skin diseases 5 0 A large majority of patients visited a hospital physician (42%: 27/64), 28% visited a General practitioner (18/64) and 23% consulted a physician remotely (15/64). -
Genes in Eyecare Geneseyedoc 3 W.M
Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.