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Clinical Haematology - Lecture notes All Lectures

Lecturer: Mr Sean Frost. All the lectures, concisely noted for easy le...
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Clinical Haematology (58315)

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Clinical Haematology

Introduction to Clinical Haematology

Red cell membrane revisited The red blood cell membrane is composed of 3 layers: the glycocalyx on the exterior, which is rich in carbohydrates; the lipid bilayer which contains many transmembrane proteins, besides its lipidic main constituents; and the membrane skeleton, a structural network of proteins located on the inner surface of the lipid bilayer. Half of the membrane mass in human and most mammalian red blood cells are proteins. The other half are lipids, namely phospholipids and cholesterol. RH as an example of epitopes as part of an antigen

Antibody production

Components of blood  Plasma (54%)  Erythrocytes (RBCs) (45%) -Contain haemoglobin and function in the transport of O2 and CO  Leukocytes (WBCs) - involved in the body’s defence against the invasion of foreign antigens.  Platelets (thrombocytes) - involved in haemostasis which forms a barrier to limit blood loss at an injured site. Both platelets and leukocytes make up 0% of blood. Functions of blood  Blood fulfils a communication role between cells: Thus, it is vital that each cell is in close communication with a blood vessel.  Gaseous exchange: Blood carries O2 from the lungs to the tissues and CO2 from the tissues to the lungs for disposal.  Delivery of other nutrients from the gut: Importantly these generally pass to the liver first for processing, and then to the tissues.  Transport of other waste products for disposal: For example, to the kidneys for excretion, or to the liver for metabolism.  Carriage of hormones: Endocrine gland secretions are carried to target tissues.  Protection against invading organisms: Blood provides an immunological function.

 Thermoregulation: Heat generated by muscles is carried to the skin.  One microliter (μl) contains:  4 to 6 million (male), 4 to 5 million (female) erythrocytes.  4,000–11,000 leukocytes  200,000–500,000 Thrombocytes (platelets) Blood Components  Plasma 2-3L in an average human male (5L of blood per average human) Straw coloured – green if a lot of neutrophils due to the haem-containing enzyme myeloperoxidase that they produce.  92% water, 8% blood plasma proteins including: glucose, amino acids mineral ions fatty acids hormones Serum albumin Blood-clotting factors (to facilitate coagulation) Immunoglobulins (antibodies)lipoprotein particles Electrolytes (mainly sodium and chloride) Plasma Proteins Plasma proteins subdivided into 3 categories:

  1. Albumin – 60% of plasma protein. Transports hormones and generates osmotic pressure.
  2. Globulin – 38% of plasma protein. Subdivided into ,  and γ globulins.  and  transport lipids and fat- soluble vitamins. γ globulins form antibodies. 3)Fibrinogen – 2% of plasma protein. Clotting factor. Haematopoiesis in humans  In humans, production of the cellular components of the blood, occurs in bone marrow exclusively. All cellular elements derived from haematopoietic stem cell (HSC). HSCs (haematopoietic stem cells) are self-renewing stem cells that can differentiate into any blood cell type. MPPs (multipotent progenitors) still have the potential differentiate into any cell type but cannot divide continuously so must be renewed by the differentiation of HSCs. CLPs (common lymphoid progenitors) differentiate into lymphoid cell types whereas CMPs (common myeloid progenitors) differentiate into myeloid cells types via the GMP (granulocyte-macrophage progenitor) or MKEP (megakaryocyte-erythrocyte progenitor).  During haematopoiesis the haematopoietic stem cells (HSC) divide, and one daughter cell remains in the bone marrow to continue renewing the HSC pool. The other daughter cell will pass through several stages of development, to become a mature blood cell and leave the bone marrow to enter the circulation.  Mesenchymal stem cells (MSC) are found in the bone marrow cavity and differentiate into a number of stromal lineages such as chondrocytes (cartilage generation), osteoblasts (bone formation), adipocytes (adipose), myocytes (muscle), endothelial cells and fibroblasts. After leaving the bone marrow and undergoing further development, activated antigen-experienced B cells differentiate into plasma cells which return to, and colonise the bone marrow cavity. Bone Marrow  Located inside spongy bone  In a normal adult, ½ of the bone marrow is haematopoietically active (red marrow) and ½ is inactive, fatty marrow (yellow marrow).  contains both erythroid (RBC), leukocyte (WBC) and platelet precursors.  Early in life most of the marrow is red marrow and it gradually decreases with age to the adult level of 50%.  In certain pathologic states the bone marrow can increase its activity to 5-10X its normal rate. replacement of the yellow marrow with red marrow Causes of hyperplastic bone marrow  This occurs in conditions where there is increased or ineffective haematopoiesis. The degree to which the bone marrow becomes hyperplastic is related to the severity and duration of the pathologic state.  Pathologic states that cause this include:  Acute blood loss in which there is a temporary replacement of the yellow marrow.  Severe chronic anaemia – erythropoiesis (RBC production) may increase to the extent that the marrow starts to erode the bone itself.  Malignant disease – both normal red marrow and fatty marrow may be replaced by proliferating abnormal cells.

White blood cell  The name "white blood cell" derives from observation after centrifugation of a blood sample,  The white cells are found in the buffy coat, a thin, typically white layer of nucleated cells between the sedimented red blood cells and the blood plasma.  The scientific term leukocyte directly reflects this description, derived from Greek λευκό (white), and κύτταρο (cell).  White blood cells are part of the immune system; they destroy and remove old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances.  The cancer of leukocytes is called leukaemia. White Blood Cells  Neutrophils -accounts for around 68% of WBC population, phagocytic and form first line defence, half- life of 6 hours so need to produce 100 billion per day for normal function!  Eosinophils – 1% of WBC population although number increased following allergic response. Attack pathogens too large for neutrophils and other defence cells.  Basophils – 0% of WBC population. Release histamine and heparin – trigger inflammation.  Lymphocytes – 25% of WBC population, key constituents of immune system. Basophil  Basophils may be chiefly responsible for allergic and antigen response  Release histamine causing inflammation.  Nucleus is bi- or tri-lobed - hard to see because of the coarse granules which hide it. •Characterized by their large blue granules.  If basophils mature at the tissue site -> mast cells Neutrophils  Defend against bacterial or fungal infection and other very small inflammatory processes that are usually first responders to microbial infection – kill foreign substances.  Their activity and death in large numbers forms pus.  Commonly referred to as polymorphonuclear (PMN) leukocytes, although technically PMN refers to all granulocytes.  Multilobed nucleus which appear like multiple nuclei.  Cytoplasm may look transparent because of fine granules that are pale lilac.  Neutrophils are very active in phagocytosing bacteria.  Die after having phagocytosed a few pathogens.  Most common cell seen in acute inflammation. Eosinophil  Eosinophils primarily deal with parasitic infections.  Eosinophils are also the predominant inflammatory cells in allergic reactions.  Important causes of eosinophilia include allergies such as asthma, hay fever, and hives; and also, parasitic infections.  Nucleus is bi-lobed.  Cytoplasm is full of granules which assume a characteristic pink-orange colour with eosin stain. Monocytes and macrophages  Monocytes share the "vacuum cleaner" (phagocytosis) function of neutrophils, but are longer lived  They also present pieces of pathogens to T cells -> CTL killing or B cells  They have the kidney shaped nucleus and are typically a-granulated. They also possess abundant cytoplasm.  Monocytes circulate for around 72 h after which they migrate to connective tissue and become tissue macrophages (M ), where they remain for up to 3 months. ᵩ  As part of this process they undergo differentiate to allow phagocytosis  Then they gain the function of removing dead cell debris

Dendritic cells

 Professional antigen presenting cells  Mop up antigen from dead and dying cells  Present it on class I and class II  Once activated, they migrate to the lymphoid node where they interact with T cells and B cells to initiate and shape the adaptive immune response.  Prime CD4+ and CD8+ cells  Bridge the gap between the innate and adaptive immune system  At certain development stages they grow branched projections, the dendrites, that give the cell its name Lymphocyte  More common in the lymphatic system. Distinguished by a deeply staining nucleus which may be eccentric in location, and a relatively small amount of cytoplasm.  The blood has three types of lymphocytes:  B cells: B cells make antibodies that bind to pathogens to enable their destruction.  T cells: –CD4+ (helper) T cells co-ordinate the immune response and are important in the defence against intracellular bacteria. Produce cytokines to direct the immune response. CD8+cytotoxic T cells are able to kill virus-infected and tumour cells through production of toxic granules. γδ T cells possess an alternative T cell receptor as opposed to CD4+ and CD8+ αβ T cells and share characteristics of helper T cells, cytotoxic T cells and natural killer cells.  Natural killer cells: Natural killer cells are able to kill cells of the body which have been infected by a virus or have become cancerous. B and T-cells  T cells (Thymus cells) and B cells (bone cells) are the major cellular components of the adaptive immune response.  T cells are involved in cell-mediated immunity  B cells are primarily responsible for humoral immunity  T cells and B cells is to recognize specific “non-self” antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells.  Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells.  Memory cells “remember” each specific pathogen encountered and are able to mount a strong(er) response if the pathogen is detected again. Natural Killer cells  NK cells distinguish infected cells and tumours from normal and uninfected cells by recognizing changes of a surface molecule called MHC (major histocompatibility complex) class I. •NK cells are activated in response to a family of cytokines called interferons.  Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells.  They were named "natural killer cells" because of the initial notion that they do not require prior activation in order to kill cells which are missing MHC class I. Blood cell turn-over  The mononuclear phagocytic system (also called the reticular endothelial system or RES) is involved in cellular destruction and it includes:  Circulating blood monocytes.  Fixed macrophages in the bone marrow, liver, spleen, and lymph nodes.  Free macrophages  These cells are involved in: Engulfing particulate matter. Processing of antigens for lymphocyte presentation. Removal of damaged or senescent cells.

Blood cell destruction and removal: The Spleen

WBC counts  The number of WBCs in the blood is often an indicator of disease.  There are normally between 4×109 and 1×1010 white blood cells in a litre of blood, making up approximately 1% of blood in a healthy adult.  Increased leukocytes numbers are called leucocytosis  A decrease below the lower limit is called leukopenia  The physical properties of leukocytes, such as volume, conductivity and granularity, may change due to activation, the presence of immature cells or the presence of malignant leukocytes in leukaemia. Platelet counts  Total count  Too little = Thrombocytopaenia  Too many = Thrombocythemia Blood films  Blood film- Blood examined under microscope  Bone marrow- Sample and examination of bone marrow Advanced diagnostics  Flow cytometry – monitor immunodeficiencies, analyse leukaemia samples by protein expression  Molecular biology – PCR - Sequencing

Haemoglobinopathies

The normal structure and biochemical function of haemoglobin

HAEMOGLOBIN
  1. O2 to the tissues
  2. CO2 to the lungs
  3. Contained inside red cells
  4. M wt 68000
  5. Synthesised in the erythroblasts and reticulocytes
  6. Consists of globin chains with a haem molecule (protoporhyrin+ Fe2+)
  7. Full molecules consist of 4 x haem+globin molecules OXYGEN DISSOCIATION CURVE
NORMAL HAEMOGLOBINS
EMBRYONIC
GLOBAL CHAIN SYNTHESIS
GENETICS

 Chromosome 11 for beta, gamma and theta  Chromosome 16 for alpha HAEMOGLOBINOPATHIES  Inherited diseases of haemoglobin are the most common single gene disorders.  WHO: 7% of the world’s population suffer from one or more haemoglobinopathies.  Many haemoglobinopathies cause no clinical disease but some like Sickle Cell anaemia and some Thalassaemia’s are life threatening.  Two Groups:  Those which have reduced rate of globin production: Thalassaemia’s  Those which give rise to structural change in the Haemoglobin: e. Sickle Cell anaemia. 2002/  National Ante Natal Sickle Cell and Thalassaemia Screening Programme.  Now combined with New-born Screening Programme

Sickle cell disease

Common structural aberrations found in haemoglobinopathies

STRUCTURAL VARIANTS

 In excess of 1000 identified variants  Sickling Disorders: Sickle cell disease and heterozygous S+ D, C, or E  Low affinity Hb’s  High affinity Hb’s  Unstable variants  Met  Hb variants  Thalassaemia like variants: Hb Lepore

HBC

HbC trait HbC disease

 &  Thalassaemia

Common structural aberrations found in haemoglobinopathies

HAEMOGLOBINOPATHIES: REDUCED SYNTHESIS

 Thalassaemia: genetic defect which brings about a reduced synthesis of one or more structurally normal globin chains.  Mutations may occur in any of the globin genes but only mutations in the α or β genes have known clinical significance gene defects have little significance δ gene defects may assist diagnosis but are not clinically significant  Widely distributed throughout the Mediterranean, Middle east and Asia

The haematological basis of clinical syndromes associated with

haemoglobinopathies

Α THALASSAEMIA (1)

 Reduced alpha globin synthesis  4 alpha genes  Hydrop’s Fetalis (4 gene deletion)  Hb H disease (3 gene deletion)  Alpha thalassaemia trait (2 or 1 gene deletion) Α THALASSAEMIA (2)  Hb Barts/Hydrops  Results in foetal loss  Hb Barts= γγ/γγ  Has a high O2 affinity  Hb Barts = 80%, remainder embryonic Hb  Useless O2 carrier  Can cause severe maternal toxaemia Α THALASSAEMIA (3)  Hb H Disease  Hb H- ββ/ββ: 5-40%  Unstable in old cells  Variable anaemia  Splenomegally  Bone changes and retarded growth  Survival into adult life interspersed with episode of severe haemolysis Α THALASSAEMIA TRAIT (4)  1 or 2 gene disorders  Mild hypochromic anaemia  No routine diagnostic test but may have reduced HbA  Often clinically silent but need to be identified for genetic screening purposes Β THALASSAEMIA (1)  Distribution similar the α thalassaemia  β gene defect but αlpha gene normal  Homozygous state result in No β globin production: β Thal major  Heterozygous state: β Thal minor  Compound heterozygous forms  Beta Thalassaemia Intermedia Β THALASSAEMIA MAJOR (2) Present in the first year of life  Poor feeding, intermittent infections, malaise  Ineffective erythropoiesis

Chronic anaemia requiring regular blood transfusions Regular transfusion result in accumulation of Fe  Adolescent growth may become retarded  Cardiac, endocrine, hepatic dysfunction  Cardiac damage may eventually lead to death B THALASSAEMIA MAJOR B THALASSAEMIA Β THALASSAEMIA (3) Management of β Thal major:  Lifelong blood transfusion  Splenectomy  Iron Chelation Complications  Deferoxamine toxicity  Growth retardation  Hypothyroidism  Diabetes Cure: Bone marrow transplant Β THALASSAEMIA (4)  β Thalassaemia Trait:  Heterozygous β gene defect, most adult haemoglobin is Hb A but have high levels of HbA  Often symptom free but can become anaemic in periods of stress i. pregnancy.  When anaemia occurs, it may become severe  As with α thal trait screening is important for detecting possible inheritance of αand β

Methodologies used to identify and qualify common variants

INITIAL DETECTION AND DIAGNOSIS
 FBC

 Blood Film  (ZPP) Ferritin  HbA  HbF  HbH if indicated FBC EXAMPLE Fe Deficiency Hb 97 (130-180) RBC 4 (4.2-6) MCV 69 (82-102) MCH 22 (27-32) MCHC 32 (31-35) Plt 331 (150-400)

B Thalassaemia Hb 120 RBC 6. MCV 65 MCH 20 MCHC 33. Plt 295

HBH

Antiphospholipid Syndrome (APS)

What is APS?

Predisposition to thrombosis and/or pregnancy loss associated with the presence of antiphospholipid antibodies.

Case 1 Severi et al (1992) ltal. J. Neurol. Sci.  Female, 44 years old – vertigo, diplopia, speech disorder and loss of strength in the right upper arm.

 protein C and S, antithrombin were normal.  Factor V Leiden mutation not present.  Diagnosis – Primary Antiphospholipid Syndrome.  Lab tests after six weeks, which confirmed the diagnosis of primary antiphospholipid antibody syndrome. – current guidelines say repeat at least 12 weeks later  Heparinised and later switched to oral anticoagulant.

APS is characterised by....  Vascular thrombosis and/or pregnancy morbidity, in association with anti-phospholipid antibodies (aPL).  These antibodies are detectable as:  anti-cardiolipin antibody  Anti-β2-glycoprotein I antibody  Lupus anticoagulant  aPL are both diagnostic and pathogenic  APS may be primary or secondary  Diverse range of presenting features  Thrombophlebitis - Painful, ‘cord-like’ inflamed area  Livedo reticularis – “net-like” subcutaneous rash  Splinter haemorrhage – small dark lines in nail  Raynaud’s syndrome – pale fingertips Advanced Avascular Necrosis Antiphospholipid Syndrome Typical presentations:  Young woman with recurrent miscarriage  Young man/woman with thrombosis but presenting features are highly variable e. see review by Hughes (2008) Autoimmunity Reviews 7;262- 6 Catastrophic APS:  Rapidly progressive widespread thrombotic disease.  Multiple organ failure.  1% of patients (followed for average of 7 years)  75% had multiple organ involvement at diagnosis.  48% mortality. Diagnostic Criteria for APS Antiphospholipid Syndrome  Thrombosis (venous or arterial)  Obstetric complications  Persistent antiphospholipid antibodies  Primary

 Secondary (esp. systemic lupus erythematosus, malignancy, medications, etc)  At least one clinical feature.  Thrombosis  Obstetric  At least one laboratory feature.  Antiphospholipid-protein antibodies Described in 1983 by Hughes et al (1983) British Medical Journal Diagnosis of APS  At least one clinical feature.  At least one laboratory feature.  Persistently positive laboratory test.  At least 12 weeks but less than 5 years between the clinical and laboratory criteria.  However, some patients will present with atypical disease and some authors talk about ‘seronegative’ APS - bear in mind the purpose of the criteria. Laboratory criteria: a) Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies). [Brandt et al 1995]. b) Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titre (i. >40 GPL or MPL, or >the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. c) Anti--2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titre >the 99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures. Classification of disease: Clinically based classification: Primary antiphospholipid syndrome:  no discernible cause.  ~50% of patients. Secondary antiphospholipid syndrome:  associated with an autoimmune disorder, most commonly systemic lupus erythematosis (SLE). The new disease definition criteria do not consider the distinction between primary and secondary disease to be important as the two have the same clinical progression. Laboratory based classification: I – more than one laboratory criteria present (any combination) II a – LA present alone. II b – aCL antibody present alone. II c – anti- 2 glycoprotein-I antibody present alone. BCSH Guidelines British Journal of Haematology – Guidelines on the investigation and management of antiphospholipid syndrome.

Who should be tested for aPL and how should this affect management of patients?

Aetiology of APS Antiphospholipid Antibodies The term “antiphospholipid antibodies” is used to refer to both:  Antibodies that recognise proteins that bind anionic phospholipid  Antibodies that bind directly to phospholipid Protein Antigens in APS  Protein antigens.  Proteins that bind to anionic phospholipid.  Main antigens  Beta-2-glycoprotein I ( 2 -GPI)  Prothrombin  Other protein antigens  Tissue plasminogen activator  Plasmin  Annexin A  Thrombin  2 -GPI  5 domains  Function unknown  Domain V binds anionic phospholipid  Domain I is the target of autoantibody  In vitro experiments show interaction with a number of platelet and endothelial cell receptors Phospholipid Antigens in APS  Phospholipid antigens.  Cardiolipin  Phosphatidylserine  Also seen in infections when they are:  Not associated with APS  Transient

 Usually low titre Aetiology of Thrombosis & Foetal Loss There is evidence that the mechanisms causing thrombosis are different to those causing foetal loss but both may involve induced endothelial TF expression.

 Prolongation of a phospholipid dependent clotting time.  Found commonly in patients with SLE.  30% lifetime risk of thrombosis. Demonstrating the Presence of Lupus Anticoagulant:  Screening test(s).  Mixing studies.  Phospholipid dependency.  Distinction from other coagulopathies by specific factor assays if needed – See Exner (1995), Greaves (2000), Wisloff (2003) Sample Preparation:  >7d after anticoagulant therapy stopped.  Minimal venous stasis.  Collect into 0 mmol/L trisodium citrate  Double centrifuge at 2000 rcf for 15 min at 15-22oC.  The following are NOT recommended:  Microfiltration through 0 filter.  Ultracentrifugation (>5000 rcf) Lupus Anticoagulant Tests:  At least 2 different methods should be used to screen:  Dilute Russell’s viper venom time  Activated partial thromboplastin time.  Dilute prothrombin time

Prophylaxis for patients with antiphospholipid antibodies

Prophylaxis for APS in pregnancy

Immunoglobulins and antibodies

BASIC IMMUNOLOGY

 Antibodies are protein molecules known as Immunoglobulins  They are found circulating in body fluids  Produced in response to the introduction of a foreign antigen  Can be autoimmune (poor recognition of self)  Combine specifically with corresponding antigen HAEMATOPOESIS REVISITED

IMMUNOGLOBULIN PRODUCTION  Immune response mechanism  Humoral as opposed to cellular  Involves white blood cells (T and B lymphocytes, plasma cells)  Antigen presenting cells (APC)  Major histocompatibility complex (MHC)  Inter leukin1 (IL-1)  Growth factor (BCGF)  Memory cells IMMUNE RESPONSE  Can be primary or secondary  Primary is less specific and may take days/weeks/months to develop  Secondary is a primed system (2 hits)  Results in highly specific antibodies usually produced fast.  Causes problems with Kidd (Jka) PRIMARY RESPONSE  First encounter with antigen  Can be slow  Usually produces IgM to start  IgG production later (except RhD)  The Primary Rh0(D) Immune Response in Male Volunteers  H. Gunson BJH Volume 32, Issue 3, pages 317–330, March 1976  Memory cells produced by immune response

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Clinical Haematology - Lecture notes All Lectures

Module: Clinical Haematology (58315)

6 Documents
Students shared 6 documents in this course

University: University of Hull

Was this document helpful?
Clinical Haematology
Introduction to Clinical Haematology
Red cell membrane revisited
The red blood cell membrane is composed of 3 layers: the glycocalyx on the exterior, which is rich in
carbohydrates; the lipid bilayer which contains many transmembrane proteins, besides its lipidic main
constituents; and the membrane skeleton, a structural network of proteins located on the inner surface of
the lipid bilayer. Half of the membrane mass in human and most mammalian red blood cells are proteins.
The other half are lipids, namely phospholipids and cholesterol.
RH as an example of epitopes as part of an antigen
Antibody production
Components of blood
Plasma (~54.3%)
Erythrocytes (RBCs) (~45%) -Contain haemoglobin and function in the transport of O2 and CO2
Leukocytes (WBCs) - involved in the body’s defence against the invasion of foreign antigens.
Platelets (thrombocytes) - involved in haemostasis which forms a barrier to limit blood loss at an
injured site. Both platelets and leukocytes make up 0.7% of blood.
Functions of blood
Blood fulfils a communication role between cells: Thus, it is vital that each cell is in close
communication with a blood vessel.
Gaseous exchange: Blood carries O2 from the lungs to the tissues and CO2 from the tissues to the lungs
for disposal.
Delivery of other nutrients from the gut: Importantly these generally pass to the liver first for
processing, and then to the tissues.
Transport of other waste products for disposal: For example, to the kidneys for excretion, or to the liver
for metabolism.
Carriage of hormones: Endocrine gland secretions are carried to target tissues.
Protection against invading organisms: Blood provides an immunological function.

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