HAEMATOLOGY BOOK PDF
PDF | Clinical Hematology, first edition is written specifically for In addition this book is also supported with review questions and quizzes. Presented by AACC and NACB. Basic Hematology. Neil Harris MD. Dept. of Pathology, Immunology and. Laboratory Medicine. University of Florida College of. as this book mentions any dosage or appli- cation, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such.
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This is a short textbook of "haematology" designed to fill the gap between Download the PDF to view the article, as well as its associated figures and tables. Following the retirement of Professor Sir John Lilleyman we needed to e find a new author for the Paediatric Haematology component of the s book. Thankfully. Hoffbrand's Essential Haematology This title is also available as an e-book. For more details, please see dovolena-na-lodi.info or scan this QR.
However, there is only one globin gene locus on chromosome 11, and therefore genes are two in number. Genes are the base sequences, which are present along the DNA strands and are necessary for the formation of a protein. The different functional areas of a globin gene are: 1. Exons and introns: The regions of DNA strand which encode amino acids in the protein product are known as exons while non-coding regions which interrupt the coding sequences are known as introns or intervening sequences.
Each globin gene contains three exons and two introns. Splice junction sequences: These are sequences at the junction of exons and introns and are required for precise splicing or removal of introns during the formation of mRNA. Promoter: The promoter region is present towards 5 end of the gene and contains sequences to which the RNA polymerase binds; it is necessary for correct initiation of transcription. Steps in the synthesis of globin: Globin synthesis involves three stepstranscription, processing of mRNA, and translation Fig.
Binding of RNA polymerase to the promoter is essential for accurate initiation of transcription. Transcription continues through exons and introns and when a chain terminating sequence is encountered, RNA polymerase gets separated from the DNA strand. A cap structure modified nucleotides is added at the 5 end of mRNA; though the exact role is unknown, capping appears to be necessary for initiation of translation.
At the 3 end a poly-A tail consisting of about adenylic acid residues is added. AAUAAA sequence at the 3 end signals the addition of poly-A tail about 20 bases downstream from the polyadenylation site.
Polyadenylation is required for stability of the transcript and its transport to the cytoplasm. Excision of Figure 1. Accurate splicing is guided by the presence of GT dinucleotide at the exon-intron boundary 5 end of intron and AG dinucleotide at the intron-exon boundary 3 end of intron.
Intron 1 is excised before intron 2. During splicing, excision at 5 exon-intron boundary occurs initially with the formation of lariat structures; subsequently excision at the 3 intron-exon boundary occurs followed by joining of exons.
Translation: This process, which occurs on ribosomes, consists of synthesis of a polypeptide chain according to the directions provided by the mRNA template. The mRNA, transcribed from the DNA template, carries the genetic code from the nucleus to the cytoplasm and determines the sequence of amino acids in the formation of a polypeptide. The tRNA transports specific amino acids from the cytoplasm to the specific locations codons along the mRNA strand; each tRNA binds and transports a specific amino acid.
The rRNA, along with certain structural proteins, constitutes the ribosome which serves as a site for protein synthesis. The different steps of protein synthesis translation are activation, initiation, elongation, and termination. Translation always begins at a codon that specifies methionine AUG, the initiator codon.
Elongation of polypeptide chain occurs when successive amino acids are added after methionine according to the pattern provided by the genetic code. During this process, movement of ribosomes occurs along the mRNA strand and ribosome slides to the next codon when an amino acid specified by preceding codon is added to the growing polypeptide chain.
Amino acids are attached to each other by peptide bonds. This is followed by release of the completed polypeptide chain from the ribosomes. The primary polypeptide chain is then organised into a secondary and a tertiary structure from interactions in its amino acids. The aerobic hexose monophosphate shunt pentose phosphate shunt is another metabolic pathway in red cells.
Apart from ATP and 2. For simplicity. The net yield of ATP from glycolysis is dependent upon the amount of glucose utilised by this shunt. In the middle of the glycolytic pathway. Metabolic pathways in red cell. Spectrin is the major cytoskeletal protein. The membrane lipids include phospholipids. The distribution of phospholipids is asymmetrical with aminophospholipids and phosphatidyl inositols located preferentially in the inner part of the bilayer and choline phospholipids in the outer part.
The important skeletal proteins are spectrin bands 1 and 2. GSH along with glutathione peroxidase detoxifies hydrogen peroxide and protects haemoglobin from oxidant damage.
Annals of Hematology
Most of the methaemoglobin produced in the normal cell is reduced to haemoglobin by NAD-linked methaemoglobin reductase.
The transmembranous and submembranous proteins constitute the red cell cytoskeleton. The red cell membrane proteins are embedded within the lipid bilayer transmembranous proteins and also form an extensive network beneath the bilayer submembranous proteins.
Red cell membrane proteins can be separated according to molecular size by sodium dodecyl sulphate polyacrylamide gel electrophoresis SDS-PAGE. The tail ends of spectrin tetramers interact with actin and this association is stabilised by protein 4. The phospholipids are arranged in the form of a bilayer. The polar head groups are oriented both internally and externally while the fatty acid chains are oriented toward each other.
Methaemoglobin reductase that is linked to NADP requires methylene blue for its activation and is more effective in druginduced methaemoglobinaemia Fig. Various metabolic pathways in the red cell are summarised in Box 1. On electron microscopy. Different bands can be visualised when stained with a protein stain such as Coomassie blue. The head ends of the spectrin dimers interact with those of the other spectrin dimers to form spectrin tetramers and oligomers.
Red Cell Membrane The red cell membrane Fig. Synthesis of 2. The cell membrane also serves to maintain the red cell volume by the cation pump. Schematic illustration of red cell membrane a hexagonal lattice. The senile red cells are recognized by macrophages of reticuloendothelial system and are destroyed mainly in the spleen. Degradation of haem liberates iron and porphyrin. Globin is converted to amino acids. The porphyrin is converted to bilirubin. The membrane provides mechanical strength and flexibility to the red cell to withstand the shearing forces in circulation.
Red cell destruction: The life span of normal erythrocytes is about days.
This process occurs within the marrow. The membrane ATPase also drives the calcium pump. The cation pump. The anchorage of the cytoskeleton to the overlying lipid bilayer is achieved by two associations: Iron is stored as ferritin in macrophages or is released in circulation where it is taken up by transferrin and transported to erythroid precursors in bone marrow.
Nuclear chromatin pattern is coarse. The nucleus contains nucleoli as in myeloblast stage. Cytoplasm contains both primary and secondary granules. Azurophil granules. Myelocyte stage is characterised by the appearance of secondary or specific granules neutrophilic. The cytoplasm stains light pink and has small.
Myelocyte is the last cell capable of mitotic division. Band stage stab form: This is characterised by band-like shape of the nucleus with constant diameter throughout and condensed nuclear chromatin.
The next stage in the maturation is promyelocyte which is slightly larger in size than myeloblast. Primary or azurophil granules appear at the promyelocyte stage. Primary and secondary granules: The neutrophil granules are of two types: Stages in the formation of mature neutrophils Myeloblast: Myeloblast is the earliest recognizable cell in the granulocytic maturation process.
The nucleus contains 2 to 5 nucleoli and nuclear chromatin is fine and reticular.
Myelocyte is a smaller cell with round to oval eccentrically placed nucleus. Cytoplasm is relatively greater in amount than in promyelocyte stage and contains both primary and secondary granules. In the metamyelocyte stage. This is followed by escape of neutrophils from blood vessels to extravascular tissue emigration.
Mature white blood cells Figure 1. Neutrophils have receptors for Fc portion of immunoglobulins and for complement. In response to infection and inflammation. Specific granules contain lysozyme. Lysosomal Chemotactic factors for neutrophils include bacterial factors.
Many organisms are identified by neutrophils after they are coated with opsonins IgG1. Phagocytosis follows which involves three steps—antigen recognition. Cytoplasm of the neutrophil extends in the form of pseudopods around the microorganism. Neutrophil kinetics. Neutrophil compartments and kinetics is shown in Figure 1. Neutrophils have a life span of only 1 to 2 days in circulation.
Function of neutrophils: After their formation. The escape of neutrophils is guided by chemotactic factors present in the inflammatory zone. After release from the marrow. Crystalloids derived from eosinophil membrane form characteristic Charcot-Leyden crystals.
Another oxygen-dependent bactericidal mechanism is independent of myeloperoxidase and involves formation of superoxide radicals. The nucleus has condensed chromatin and is covered by granules. Tissue mast cells are of mesenchymal origin.
Maturation time for eosinophils in bone marrow is 2 to 6 days and half-life in blood is less than 8 hours. The last step in phagocytosis is killing of micro-organism. Eosinophils Eosinophil forms via same stages as the neutrophil and the specific granules first become evident at the myelocyte stage. Basophils Basophils are small. Mast cells in connective tissue or bone marrow differ morphologically from basophils in following respects: The granules contain major basic protein.
Upon reaction of antigen with membrane-bound IgE. Oxygen-dependent mechanism involves conversion of oxygen to hydrogen peroxide by oxidase in phagolysosome. The next cell is promonocyte which has an oval or clefted nucleus with fine chromatin pattern and 2 to 5 nucleoli. The size of the eosinophil is slightly greater than that of neutrophil.
In tissues. Oxygen independent bactericidal mechanism occurs in lysosomal granules and is mediated by substances such as lysozyme. Basophils are also involved in some cutaneous basophil hypersensitivity reactions. Monocytes The initial cell in development is monoblast.
Basophils bear surface membrane receptors for IgE. Eosinophilic peroxidase along with iodide and hydrogen peroxide may be responsible for some defense against helminthic parasites. The nucleus is often bilobed and the cytoplasm contains numerous.
Basophil granules contain histamine. The mononuclear phagocyte system with irregular shape. Macrophages also recognise and phagocytose some target substances by their surface characteristics. Activated macrophages secrete a variety of biologically active substances: Activated macrophages are larger and have enhanced metabolic and phagocytic activity. Macrophages have receptors for Fc portion of IgG and C3b and cause phagocytosis of organisms that are coated with these substances.
Monocytes circulate in blood for about 1 day and then enter and settle in tissues where they are called as macrophages or histiocytes. Coagulation factors. Prostaglandins and leukotrienes which are chemical mediators in inflammation. Cytoplasm is abundant. Macrophage phagocytosis is slower as compared to neutrophils. Complement proteins. In some organs. Oxygen-derived free radicals—hydrogen peroxide. Differences between B and T lymphocytes are presented in Table 1.
Table 1. The function of B lymphocytes is production of antibodies after differentiation to plasma cells. The cytoplasm is basophilic. Origin Lymphoid stem cell in bone marrow 2. Lymphocytes These are of two types—small and large. Percentage in peripheral blood 5. Nuclear chromatin is dense and arranged in a radiating or cartwheel pattern. The nucleus is round or slightly clefted with coarse chromatin and occupies most of the cell. Initial development occurs in primary lymphoid organ bone marrow from where B cells migrate to the secondary lymphoid organs lymph nodes and spleen where further differentiation occurs on antigenic stimulation.
B cells undergo differentiation and proliferation to form plasma cells and memory cells. Function CD Location in lymph node 6. Plasma cells secrete immunoglobulins while memory cells have a lifespan of many years and upon restimulation with the same antigen undergo proliferation and differentiation.
B Lymphocytes B lymphocytes arise from the lymphoid stem cells in the bone marrow. Surface receptor 4. Surface antigens 3. On activation by antigen. Plasma cell is a round to oval cell with eccentrically placed nucleus and deeply basophilic cytoplasm. Their nucleus is similar to that of small lymphocytes but their cytoplasm is relatively more and contains few azurophilic dark red granules.
On immunophenotyping. Each immunoglobulin molecule consists of two heavy chains and two light chains. Antigen-independent development occurs in bone marrow while antigen-dependent development occurs in peripheral lymphoid tissues.
Light chain gene rearrangement: During light chain gene rearrangement. From the C region. Heavy chain gene rearrangement Fig. The VDJ thus formed codes for amino acid sequence in variable region. There are 5 classes of immunoglobulins: During development of B cells. Both heavy and light chains have constant and variable regions. To react with a vast array of antigens. Second immunoglobulin gene rearrangement can occur in activated B cells in which switching to new C segment of heavy chain gene occurs.
The antigen-specificity of a particular immunoglobulin molecule depends upon amino acid sequence in the variable region antigen-binding site.
There are several gene segments in V. In heavy chain genes. An immunoglobulin gene consists of V Variable and J Joining exons which code for amino acid sequences in variable region. There are two stages of B cell development: The amino acid sequences in constant regions of heavy and light chains remain same for particular class and do not determine antigen specificity. The heavy chain genes are located on chromosome Switching does not affect VDJ exon so that antigen specificity is not altered.
Important features in B cell ontogeny are outlined below. During B cell development. This causes change in the class of the immunoglobulin molecule. B cell ontogeny Fig. The unrearranged heavy and light chain genes are present in all the cells of the body germ-line configuration.
V and D regions other than V3 and D2 are deleted. The mRNA formed is translated into a m heavy chain in cytoplasm ii. According to the fundamental theory of lymphoid neoplasms. T lymphocytes T lymphocytes originate from the progenitor cells in the bone marrow and undergo maturation in thymus. In activated B cells. The rearranged gene is transcribed into mRNA and intervening sequences between J3 and Cm are spliced.
In pre-B cell. Immunoglobulin heavy chain gene rearrangement. With development and maturation new antigens are expressed while some of the previous ones are lost.
Rearrangement of immunoglobulin genes and immunoglobulin expression: Initially there is rearrangement of heavy chain genes which is followed by rearrangement of light chain genes.
Cell surface antigens: After their release from thymus. There is a sequential appearance of antigens on developing B cells: Plasma cells do not have surface expression of immunoglobulin but synthesize and secrete large amounts of immunoglobulins of one class. This is followed by rearrangement of light chain genes.
Plasma cells express specific antigens such as CD38 Fig. Cytotoxic T cells recognize antigen in association with MHC class I molecules and play an important role in cell-mediated immunity.
As shown at the bottom. Helper-inducer T cells regulate the functions of B cells and cytotoxic T cells. T cell receptor TCR: The T cell receptor complex consists of seven polypeptide chains. There are two major subsets of mature T cells: T helper-inducer cells and T cytotoxic cells.
Normal stages of B cell development showing sequential expression of various antigens and heavy and light chain gene rearrangement.
Diffuse large B cell lymphoma. Mucosa associated lymphoid tissue. T helperinducer cells recognise antigen presented by antigen-presenting cells in association with MHC class II molecules. The rearranged gene is transcribed into mRNA. Progenitor T cells from the bone marrow are transported to thymus where they undergo maturation.
As there are a number of V. T cell receptor complex In a minority of T cells. TCR gene rearrangement: The genetic structure of TCR bears resemblance to that of immunoglobulins. T cell ontogeny Fig. Although all somatic cells contain T cell receptor gene in germ-line configuration. The mature T cells are released from thymus. One segment each from V. Rearrangement of other polypeptide chain occurs similarly. During maturation. These cells do not require previous exposure or sensitisation for their cytotoxic action.
Class II antigens: Class I antigens: Genes at HLA-A. The antigens are called as HLA because they were first detected on white blood cells.
Almost all nucleated cells possess class I antigens Fig. Types of HLA antigens: Class II antigens are present on monocytes. Stages of T cell development. There are numerous allelic genes at each locus which makes the HLA system extremely polymorphic.
If particular antigen is present on lymphocytes. These lymphocytes are then added to known specific antisera in microwell plates and incubated to allow the antibodies to bind to target antigens.
A vital dye eosin Y or trypan blue is then added to differentiate living. In a given population. Class III genes encode certain complement components and cytokines tumour necrosis factor. Significance of HLA antigens: HLA antigens are responsible for alloimmunization against platelet antigens and refractoriness to platelet transfusions.
The HLA genes are closely linked and are inherited by an individual as a haplotype from each parent. Complement is added to the lymphocyte-antiserum mixture followed by further incubation. Tests for detection of HLA antigens: In this test.
Lymphocytotoxicity test: Class I HLA antigens are detected by lymphocytotoxicity test. During incubation in culture. As these responder cells have been primed i. This is because class II antigens are present on B lymphocytes and not on unstimulated T cells. It is based on mixed lymphocyte culture. DNA analysis: Allelic genes at HLA-D loci can be identified by allele-specific oligonucleotide probe analysis. This test is used for detection of class II antigens.
Lymphocytes from two different individuals are cultured together. Primed lymphocyte typing PLT test: Lymphocytes from one individual are inactivated by irradiation or by mitomycin C before the test to suppress their division. Damaged cells take up the dye due to the increased permeability of injured cell membrane while living cells remain unstained.
After 5 to 7 days 3H-thymidine is added to the culture and radioactive material incorporated into the dividing responder cells is quantitated. Neutrophil-specific antigens play an important role in immune neutropaenias and in febrile nonhaemolytic transfusion reactions. In this method the culture of lymphocytes is extended for 2 weeks during which death of stimulator cells occurs and proliferation of responder cells halts.
Separation of B lymphocytes is usually achieved by magnetic beads. With the advent of polymerase chain reaction technology. These are NA1. The amount of radioactive thymidine incorporated into the dividing cells is proportional to DNA synthesis. The area J of the heavy chains in the constant regions between CH1 and CH2 domains is flexible and is called hinge region.
The H and L chains are linked together by disulfide s-s bonds. Each Fab fragment antigen binding fragment contains amino terminal portion of H chain and complete light chain and has the antigen-combining site Fig. Five classes of immunoglobulins are recognised based on the type of H chain: Amino acid composition in the carboxy terminal region of heavy chain and light chain is the constant region. Kappa and lambda chains are present in 2: Structure of Immunoglobulins The immunoglobulin molecule consists of two identical heavy H chains and two identical light L chains.
Broken line indicates site of papain digestion. Each immunoglobulin molecule can be digested by a proteolytic enzyme papain just above the disulphide bond joining the two heavy chains into three parts: They are produced by plasma cells. Structure of immunoglobulin molecule. The fragment. The variable region of the molecule VL and VH is the specific antigen-binding site and is in the amino-terminal part of the molecule.
Each chain has a constant and a variable region Fig. IgG1 and IgG2. IgD and IgE: Both are present in trace amounts in serum and are monomeric. This has high molecular weight and is also called as macroglobulin due to its large size. There are four subclasses of IgG: IgA is present mostly in body secretions such as gastrointestinal and respiratory mucosal secretions. Alloantibodies vs autoantibodies: Alloantibodies are those which are produced by an individual against antigens present in another individual of the same species.
Autoantibodies are those. Most IgG antibodies are of warm type while most IgM antibodies are of cold type. IgG is capable of fixing complement with order of efficacy being IgG3. IgM molecules have a pentameric structure i. IgM is highly efficient in binding complement. Secretory IgA is mostly IgA2 and exists as a dimer. IgM is the first antibody produced in response to the antigen primary response. Most IgD is expressed on the surface of resting B lymphocytes where it serves as an antigen receptor.
Serum IgA. The order of efficiency of complement binding of immunoglobulins is IgM. Most IgE is bound to basophils or mast cells through heavy chain. IgG is the monomer of the basic immunoglobulin structure. In contrast to IgG.
When a specific antigen combines with IgE. The foetus is able to produce IgM after maturation of its immune system. There are two subclasses of IgA: IgA1 and IgA2. IgG is usually produced during secondary immune response. There are no receptors on macrophages for IgM. The foetus cannot synthesize IgG and therefore IgG antibodies in the newborn represent those passively gained from the mother.
It is the only immunoglobulin. IgM cannot cross the placenta. Warm vs cold antibodies: A single molecule of IgM can bind complement while two molecules of IgG lgG doublets are necessary for complementbinding. Characteristic features of different immunoglobulins are presented in Table 1. IgG4 cannot bind complement in the classical pathway. The complements are activated in the following order: The C4b2a complex C3 convertase is formed.
Binding of antibody to antigen causes exposure of complement-binding site on immunoglobulin. C3b is not enzymatically active by itself. C5 convertase cleaves C5 into C5a and C5b.
Essentials of HAEMATOLOGY.pdf
Binding of only a single IgM pentameric molecule or of IgG doublet to an antigen are necessary for complement activation. Structure Pentamer Monomer Dimer secretions. Some C3b joins C4b2a to form C4b2a3b C5 convertase.
Half-life days 5 21 6 2 3 6. C3dg cannot adhere to macrophages because macrophages do not have receptors for C3dg. C3b however is rapidly degraded into C3dg. The activated C1 cleaves C4 to form C4a and C4b.
The MAC creates pores in red cell membrane through which water enters into red cells. Monomer monomer serum Monomer 5. C4a is released into the body fluid while C4b attaches to the red cell membrane.
C5a is released in circulation. This process occurs on the surface of target cells e.
Main function Primary immune Secondary Mucosal immunity response immune response Anaphylactic reaction Unknown e Complement Complement are serum proteins which when activated react in an orderly manner with each other to cause immunologic destruction of target cells lysis or phagocytosis.
Molecular weight The C3a is released into plasma while C3b attaches to the cell membrane. There are three pathways of complement activation: The C4b2a complex attached to cell membrane has enzymatic activity and can cleave several hundred C3 molecules.
Activated C1 also cleaves C2 to form C2a. Once C3b is converted to C3dg. Regulation of Complement Activity Following factors act as a control mechanism against prolonged complement action: Mannose-binding lectin pathway: Mannose-binding lectin directly binds to target cell surface.
Properdin may stabilise C3bBb. C3 is activated directly with no role of earlier complement components. C3 is being continuously cleaved at low level. Alternate pathway plays an important role in initial defense against infection in nonimmune persons. The complement pathway. C3 can be activated by endotoxins. It does not require antigen-antibody reaction. Solid arrow indicates transformation of a complement component. Factor B is cleaved by factor D to form C3bBb. A serum protein called properdin.
Specific inhibitors of activation of some complement components particularly C1 and C3 are present in plasma. C3bBb splits C3 to generate more C3b thus forming an amplification loop. Dashed arrow indicates enzymatic action of complement component that causes cleavage of that component Alternate Pathway In alternate pathway. C3a and C5a are anaphylatoxins and increase vascular permeability.
Acute inflammation: Certain complement components play a role in acute inflammation. Sometimes neutrophils or other marrow cells are seen traversing through the cytoplasm emperipolesis. Each meakaryocyte produces to platelets.
Mature megakaryocytes extend long and slender cytoplasmic processes proplatelets between endothelial cells of sinusoids in bone marrow and platelets are released from fragmentation of these processes. Enzymatically active complement components have a very short life and are rapidly degraded to inactive forms.
This refers to nuclear division with cytoplasmic maturation but without cell division. Megakaryoblasts stage I are the earliest morphologically recognizable precursors. It is divided into four stages Fig. Active fragments are rapidly cleared from circulation. Macrophages have specific receptors for C3b and thus target cells coated with C3b are recognised and phagocytosed by them Opsonins are substances which when present on the surface of the antigen such as red cells facilitate immune phagocytosis.
Target cell lysis by membrane attack complex C5b Various Effects of Complement Activation 1. As the cell matures from megakaryoblast to the megakaryocyte. A unique feature of thrombocytopoiesis is endomitosis. Mature megakaryocytes stage IV are of similar size. The megakaryocytes possess well-developed membrane.
Following vessel injury. Formation and release of platelets from a megakaryocyte demarcation system. A humoral factor. Upon complete maturation. There is evidence that some of the megakaryocytes are carried to the lungs where platelets are released. The process of dissolution of blood clot is called as fibrinolysis. During secondary haemostasis. Although formation of blood clot is necessary to arrest blood loss. Megakaryopoiesis Figure 1. The roles of vascular wall. Primary haemostasis is the initial stage during which vascular wall and platelets interact to limit the blood loss from damaged vessel.
Certain factors synthesised by endothelial cells promote haemostasis and include tissue factor. Platelet activating factor induces aggregation of platelets Fig. Deficiency of protein C or protein S is associated with tendency towards thrombosis.
Normal platelet count in peripheral blood is 1. Heparin-like substances on the surface of endothelial cells potentiate the action of antithrombin.
Endothelial cells also synthesise tissue plasminogen activator. Under light microscope. Binding of thrombomodulin to thrombin causes activation of protein C. Platelets remain viable in circulation for approximately 10 days. These include—thrombomodulin. Another vascular factor promoting haemostasis is vasoconstriction of small vessels following injury. These granules may Figure 1.
Cytoplasmic granules are often visible. Role of blood vessels in haemostasis. Protein S is a cofactor for protein C. Tissue factor or thromboplastin activates extrinsic system of coagulation.
About one-third of the total platelets in the body are in the spleen and remainder in peripheral blood. Platelets Platelets are derived from cytoplasmic fragmentation of bone marrow cells called megakaryocytes. Subendothelial collagen promotes platelet adhesion and also activates factor XII intrinsic pathway. C and is a potent inhibitor of coagulation. An extensive open canalicular system. Peripheral zone: Exterior or surface coat glycocalyx overlies the cell membrane.
Microfilaments have contractile function. It functions as a route through which platelet contents are secreted outside the cell. The cell membrane is a trilaminar membrane composed of proteins. The chief membrane lipids are phospholipids which are arranged as a bilayer. Sol-gel zone: Microtubules provide structural support to the platelets. It is made of proteins.
The phospholipids play an important role in prostaglandin synthesis and in platelet procoagulant activity. Ultrastructure of Platelets Ultrastructurally. Some of the glycoproteins are polysaccharide side chains of the integral membrane proteins while others are adsorbed from the plasma.
Ultrastructure of platelet The dense tubular system. Important platelet membrane glycoproteins and their functions are as follows: Gp Ib-IX-V: This is a constitutively active receptor that mediates vWF-dependent adhesion of platelets to subendothelial collagen. HLA class I antigens induce alloimmunisation and cause refractoriness to platelet transfusions when platelets are obtained from random donors.
Gp Ia-IIa: Constitutively active receptor for collagen and mediates platelet adhesion independent of vWF. The platelet-specific antigen systems are now known as human platelet antigen HPA systems. On activation. This means binding of platelets to nonendothelial surfaces.
Role of Platelets in Haemostasis Activation of platelets refers to adhesion. Also receptor for vWF. Congenital absence of glycoprotein receptor GpIb Bernard-.
Platelet Membrane Glycoproteins The cell membrane contains integral membrane glycoproteins Gp. Platelet specific antigens play an important role in neonatal alloimmune thrombocytopaenic purpura NATP and in post transfusion purpura. Platelet organelles are alpha granules. Contents of platelet organelles are shown in Table 1.
ADP released from platelets or from damaged cells binds to specific receptors on platelet surface. ADP released from dense granules promotes platelet aggregation.
Thromboxane A2 has a very short half-life and is degraded into thromboxane B2 which is biologically inactive. Platelet adhesion to subendothelial collagen. Platelet factor 4 released from alpha granules neutralises the anticoagulant activity of heparin while platelet-derived growth factor stimulates proliferation of vascular smooth muscle cells and skin fibroblasts and plays a role in wound healing. A configurational change in the membrane occurs so that receptors for fibrinogen GpIIb and IIIa become exposed on the surface.
In this process. This shape change is due to reorganisation of microtubules and contraction of actomyosin of microfilaments. TxA2 also induces aggregation of other platelets and local vasoconstriction. With activation. These are then converted to thromboxane A2 by thromboxane synthetase.
This causes inhibition of adenyl cyclase and reduction in the level of cyclic AMP in platelets. TxA2 causes shape change and stimulates release reaction from alpha and dense granules. Activated platelets also synthesise and secrete thromboxane A2 TxA2 Fig. Binding of fibrinogen Platelet agonists such as ADP. Platelets normally circulate as round to oval disc-like structures.
This may be defined as binding of platelets to each other. Release reaction secretion: Immediately after adhesion and shape change. These phospholipids play active role in coagulation by providing surface for interaction of some coagulation factors. The activated platelets release ADP and TxA2 and so a self-sustaining reaction is generated leading to the formation of a platelet plug. Critical coagulation reactions for which activated platelets provide a negatively charged phospholipid PL surface are shown in Figure 1.
Platelet procoagulant activity: When platelets are activated. Synthesis of thromboxane A2. Modes of action of certain antiplatelet drugs are also shown Figure 1. Platelet aggregation. Fibrin and aggregated mass of platelets at the site of injury constitute the haemostatic plug.
This may explain the absence of bleeding diathesis in persons with F XII deficiency. Thrombin generated from activation of coagulation system is a potent platelet-aggregating agent and also converts fibrinogen to fibrin.
Factors XII. Fibrinolytic system: Coagulation system: Factors I. F XIII. According to the International System of Nomenclature. The coagulation factors have been assigned Roman numerals according to the order of their discovery.
Except calcium and thromboplastin. Attachment of coagulation factors to phospholipid is essential for coagulation reactions to occur. When coagulation factors become activated. In the absence of vitamin K. Plasma Proteins in Haemostasis Plasma proteins in haemostasis can be divided into following groups: Calcium in turn. Factors II. Inhibitor system: Protein C. Platelet procoagulant activity. Platelets provide surface for some important coagulation reactions In addition platelets also secrete calcium.
Activation of fibrinogen denotes cleavage of fibrinopeptides A and B from the molecule with formation of fibrin. Coagulation System A number of coagulation proteins factors participate in coagulation reactions.
Thrombin releases fibrinopeptides A and B from these chains to form fibrin monomers Fig. F XIII is derived from megakaryocytes. Laki-Lorand factor Fletcher factor Fitzgerald factor Prekallikrein High molecular weight kininogen The liver is the site of synthesis of most coagulation factors. Thrombin splits fibrinopeptides A and B from fibrinogen to form fibrin monomers. Fibrinogen consists of three domains—two outer D domains and a central E domain.
Fibrinogen is an acute phase reactant and its concentration rises in a variety of non-specific conditions such as inflammation. Fibrinogen Molecular weight MW Prothrombin MW Thrombin has multiple functions in haemostasis Fig. About one-fifth of the FV in blood is stored in platelet alpha granules.
Tissue injury results in the formation of a complex between single chain form of F VII. It is composed of two parts: Thrombin is a powerful platelet agonist.
F V is activated by thrombin and functions as a cofactor in the conversion of prothrombin to thrombin by the prothrombinase complex. Thrombin activates protein C. This complex can also activate F IX. A1 and A2 domains constitute the heavy chain of the molecule while A3. B is the connecting region Fig. Tissue factor is distributed in all tissues. Factor V MW C approx 12 hours: C and von Willebrand factor.
It is kilobases long and consists of 26 exons.
F VIII: C is the low molecular weight portion which has procoagulant activity and its synthesis is X-linked. C and also mediates adhesion of platelets to the subendothelium at sites of vessel damage. F V is a heat-labile factor. Tissue factor is required for activation of F VII in extrinsic pathway. The RNA is approximately 9 kilobases in length. Multiple actions of thrombin in haemostasis 4.
F VIII gene has 26 exons and 25 introns. Polypeptide chain encoded by the gene has six regions: Factor X MW F XIII is a transglutaminase. In contrast to all other coagulation factors. F XII plays a role in contact activation of coagulation system. High molecular weight kininogen MW Kallikrein plays a role in chemotaxis and in activation of fibrinolysis.
F XII is activated when it comes in contact with substances such as collagen. Kallikrein in turn further activates F XII and thus serves to amplify the initial stimulus. Prekallikrein is activated by F XIIa to kallikrein. It promotes contact activation. Mechanism of Blood Coagulation Scheme of blood coagulation is divided into intrinsic.
Factor XI MW Neutrophil compartments and kinetics is shown in Figure 1. Sometimes additional information can be derived by observing the colour of the plasma pink in haemolysis, yellow in the presence of jaundice, colourless in iron deficiency anaemia and the thickness of the buffy layer thick buffy layer indicates leucocytosis, thrombocytosis, or leukaemia.
Smears can also be prepared from the buffy coat layer for demonstration of blast cells and for malaria parasites if they are few in number in blood. To obtain the haemoglobin concentration of the unknown sample, its absorbance is compared with that of the standard cyanmethaemoglobin solution the haemoglobin concentration of which is known. Factors I. Thrombin splits fibrinopeptides A and B from fibrinogen to form fibrin monomers. Each immunoglobulin molecule can be digested by a proteolytic enzyme papain just above the disulphide bond joining the two heavy chains into three parts: Excision of Figure 1.
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