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HAEMOSTASIS - Coggle Diagram

- - - - ELECTROPHORESIS
        
        Polyacrylamide gels
        
        Cellulose acetate – most common in clinical laboratories. After staining- 5 bands – albumin, α1, α2, β and γ.
        
        Stained strip is called electrophoretogram.
        
        Characteristic changes in the amount of one or more of these 5 bands are found in many diseases.
  - - - To prevent too much intravascular fluid from being forced into the tissue spaces, hydrostatic pressure is opposed by intravascular colloid osmotic pressure from plasma proteins.
        
        If the conc. of plasma proteins is markedly diminished (e.g. due to severe protein malnutrition) fluid will accumulates in the extravascular tissue spaces- a condition called edema.
  - - - Values of radioactivity plotted against time, half-life (time for radioactivity to decline from its peak value to one-half value) can be calculated.
        
        Half-lives for albumin and haptoglobin in normal healthy adults are approx. 20 and 5 days respectively.
        
        E.g. of altered half life of a protein – gastrointestinal diseases – regional ileitis (Crohn’s disease) where considerable amount of plasma proteins including albumin may be lost into the bowel through the inflamed intestinal mucosa.
        --> *the amount of substance inside the living organism is metabolized and eliminated half of its initial amount by normal biological process.
  - - - C-reactive protein (CRP)
        
        Major component of acute phase response and a marker for bacterial infection.
        
        Synthesized in the liver, 5 polypeptide subunits, ~130kD
        
        Minute quantity in normal serum (<1mg/L)
        
        ↑ during inflammation, infection, trauma
        
        Function: mediate binding of foreign polysaccharides, phospholipids and complex polyanions and also activating complement via classical pathway.
        
        E.g. binds to C-polysaccharides of bacterial membrane → initiate classical complement system → opsonization → phagocytosis.
  - - - The complement system can be activated by two different pathways:
        1) the classical complement pathway (activated by the binding of antibody molecules eg IgG and IgM to a foreign particle )
        2) the alternative complement pathway (activated by invading micro-organisms and does not require antibody )
        
        In both cases, a cascade of events follows
        
        The complement system provides the actual protection from the response while the interaction of antibodies and antigen provides the specificity of the response.
        
        Antibodies will show the target, complement destroys it.
  - - - Most abundant- 60% of plasma proteins ~4.5g/dL
        
        Single polypeptide chain (585 aa), 69kD
        
        Synthesized in the liver.
        
        ↓ in protein malnutrition – Kwashiorkor
        
        ↓ during inflammation, trauma, burn etc.
        
        ↓ in liver diseases – cirrhosis, hepatoma.
        
        Half-life – 20 days, in acute liver disease – albumin is normal.
        
        FX
        
        Maintain osmotic pressure.
        
        Maintain balance between intra and extra cellular fluid. fluid will accumulates in the extra vascular tissue spaces- edema.
        
        Ability to bind to various ligand
        
        Free fatty acid (FFA), calcium steroid hormones, bilirubin and tryptophan.
        
        Transportation
        
        Copper, drugs- sulphonamides, penicillin G, dicumarol and aspirin.
    - - Single chain protein, 394 aa, ~ MW 52,000
        
        Major component (>90%) of α1 fraction of human plasma.
        
        Synthesized in the liver (hepatocytes) and macrophages.
        
        Function: serine protease inhibitor of human plasma.
        
        Also inhibits trypsin, elastase and other proteases by forming complexes with them.
    - - Emphysema- a degenerative disease that usually develops after many years of assault on lung tissue from cigarette smoking and other air pollutants - difficulty in breathing.
        
        Long-term exposure causes inflammatory response in lungs resulting in narrowing of airways & breakdown of lung tissues.
        
        Smoking cigarette will inhibit AAT – function is to protect lungs from the neutrophil elastase -accelerating emphysema.
        
        Other causes: Air pollution
        
        Rare genetic disorder- AAT deficiency liver disease
        
        PATHOENESIS
        
        the protease-antiprotease hypothesis explain effect of cigarette smoking in the production of centriacinar emphysema
        
        smokers have accumulation of neutrophils in alveoli
        
        smoking stimulates release of elastase
        
        smoking enhace elastase act in macrophages --> macrophage elastase is not inhibited by α1-antitrypsin (AAT)
        
        tobaco smoke sontains reactive O2 species w/ inactivation of protease
    - - ~ 10% Hb is degraded daily and released into circulation.
        
        ~ 90% is present in old and damaged red blood cells, which are degraded.
        
        Function – binds to extracorpuscular hemoglobin (Hb) forming a noncovalent complex Hb-Hp, preventing free Hb from entering kidney.
        
        MW Hb- 65,000, MW Hp (Hp 1-1) – 90,000 ; MW complex ~155,000.
        
        Free Hb passes through glomerulus of kidney & tends to precipitate.
        
        However the complex is too large to pass through ∴prevent the loss of free Hb into the kidney.
        
        Conserves the valuable iron.
        
        Human Hp exists in 3 polymorphic form – Hp 1-1, Hp 1-2 and Hp 2-2.
        
        2 genes, Hp1 and Hp2 No functional differences among theses polymorphic forms.
        
        Levels of Hp vary & have diagnostic use. Low levels of Hp are found in hemolytic anemias- half life Hp ~5 days but half life of Hb-Hp complex is ~90mins∴it is rapidly removed from plasma by hepatocytes.
        
        Clearance is 80x faster than normal.
        
        Hp is an acute phase protein and its plasma level is elevated in a variety of inflammatory states.
        
        There are other plasma proteins that binds to heme but not hemoglobin.
        
        Hemopexin (β1-globulin) binds to free heme.
        
        Albumin will bind some metheme (ferric heme) forming methealbumin which transfers metheme to hemopexin.
    - - Function: transport 90% copper (Cu) (blue), 10% of Cu by albumin.
        
        Each ceruloplasmin will bind to 6 atoms of Cu very tightly, so Cu not readily exchangeable.
        
        Cu – cofactor for enzyme
        
        Amount ↓ in liver disease. In Wilson’s disease, an inborn error of copper metabolism, liver can’t synthesize ceruloplasmin →deposition of copper in liver causing liver cirrhosis.
        
        In the brain causing basal ganglia degeneration & in cornea producing characteristics Kayser Fleischer rings.
    - - FX
        
        Antiprotease, inhibit pancreatic proteases
        
        Transport Zn2+
        
        Binds cytokines (e.g. TGF-β, IL-6 and TNF-α)
    - - TRANSFERRIN
        
        Apparent MW 80,000.
        
        Glycoprotein and synthesized in the liver. >20 polymorphic forms of transferrin (Tf).
        
        Function: transports iron to where it is required (e.g from gut to bone marrow and other organs). (2 moles of Fe3+(ferric) /mol Tf)
        
        Tf-intestines (Fe2+(ferrous) →Fe3+ by enzyme in caeruloplasmin)
        
        Free iron is toxic but association with Tf will diminished its potential toxicity.
        
        Iron is important because it is needed by many hemoproteins hemoglobin, myoglobin and cytochromes.
        
        Tf will bind to receptors on the cell surfaces, enters the cells through endocytosis.
        
        Acidic pH inside lysosome, Fe3+ dissociates from transferrin, leaving as apoTf, reutilized.
      - FERRITIN
        
        24 subunits of 18,500, MW 440,000kDa.
        
        Contains 23% iron & apoferritin (protein moeity free of iron)
        
        Stores iron (e.g in the liver, kidney and heart) Reduced in anemia Increased in hemochromatosis (hereditary disease-improper processing of dietary iron causing accumulation of iron in body tissues &leads to organ dysfunction (liver, skin & pancreas).
        
        Moderate increase in inflammation.
        
        Hemosiderin- abnormal microscopic pigment from degraded ferritin (deposits of iron).
        
        Low density lipoprotein (LDL, β globulin)
        
        A class of lipoprotein particles.
        
        Precursor- VLDL, produced by the liver.
        
        Transport cholesterol from liver to arteries.
        
        Increased level will cause artherosclerosis
        
        Also known as bad cholesterol HDL.
    - - Due to malignant proliferation of abnormal monoclonal Ig → paraproteinemia.
        
        Paraprotein band seen in electrophoretic pattern.
        
        Urine protein electrophoresis → Bence Jones protein (light chain myeloma), may cause renal failure. Bone lesions affect the skull, vertebrae, ribs and pelvis.
        
        There may be generalised osteoporosis and pathologic fractures.
        
        Other common findings, anemia and hypercalcemia.
  - - - B lymphocytes (from bone marrow cells in higher animals)
        
        B cells – responsible for synthesizing and secretion of antibodies (Igs).
        
        E.g of B cells- plasma cells
        
        IgG
        
        Main antibody, 75% in plasma, 160kD, T1/2 22days.
        
        Function:
        
        eliminate small soluble antigenic proteins through aggregation,
        
        Enhance phagocytosis, e.g bacteria
        
        Activates complement system→enhance killing of bacteria
        
        The only ab that can cross placenta →provide protection against infection for fetus and newly born baby (first 6 months).
        
        Increased in repeated infections.
        
        IgA
        
        7-15% pf plasma Igs, T1/2 6 days
        
        Monomer, dimer and trimer form
        
        Found in parotid(saliva), bronchial and intestinal secretions.
        
        Also found in tears and sweat.
        
        Major component in colostrum (mother’s early milk)
        
        Function:
        
        Primary immunologic barrier against pathogen invasion of mucous membrane.
        
        It can promote phagocytosis and activate complement via the so-called alternate pathway.
        
        IgM
        
        5-10% plasma Igs, 971 kDa, T1/2 5 days.
        
        Pentamer --> Found in intravascular space, lesser amount in secretions usually associated with secretory component.
        
        First ab to be synthesized after antigenic challenge e.g infections.
        
        Because of its high number of antigen binding sites (5), it is an effective agglutinator of antigen.
        
        This is important in the initial activation of B-cells, macrophages and the complement system.
        
        MINOR
        
        IgD
        
        0.5% plasma Igs, MW 190 kDa
        
        Different from standard structure with high carbohydrate content.
        
        Found on the surface of mature B cell.
        
        Function: uncertain, may play a role in activating and suppressing lymphocyte activity.
        
        Rare cases of isolated IgD deficiency seemed to be associated with no obvious pathology.
        
        IgE
        
        Trace amount, 200kDa
        
        Similar to IgD in unit structure.
        
        Found on mast cells and basophils
        
        Function: involves in hypersensitivity (allergic reaction e.g asthma & eczema), release of mediators (e.g histamines) from mast cells upon exposure to antigen.
        
        Defends against parasitic infections by causing release of enzymes from eosinophils
        
        Do not activate complement system.
      - T lymphocytes (from thymic origin).
        
        Involved in a variaty of cell-mediated immunologic processes e.g hypersensitivity reaction, defense against malignant cells and viruses
      - Antibodies – proteins produced by immune system that have defined specificity for immunogens.
        
        Immunogens- foreign particles that can stimulate synthesis of Igs.
        
        Antigen – agents that can bind with antibodies.
        
        Igs- uniquely diverse group of molecules that can recognize and react with a wide range of specific antigenic structures (epitopes) and give rise to a series of effect that will eventually eliminate the presenting antigens.
        
        Some Igs have additional effectors functions e.g IgG is involved in complement activation.
        
        STRUCTURE
        
        Y shaped: 4 polypeptides, 2 light chains & 2 heavy chains bound by disulphide bonds.
        
        Constant region (CH &CL)
        
        Variable regions (VH & VL)– amino acid sequences at this region specifies which antigen to bind.
        
        Heavy chain specifies classes of Ig,
        
        IgG- γ heavy chain
        
        IgD - δ heavy chain
        
        IgA - α heavy chain
        
        IgE - ε heavy chain
        
        IgM - μ heavy chain
        
        Light chains : two light chains either κ or λ may be found in any one class of immunoglobulins, never a mixture.
        
        In human, κ chains are more frequent than λ chains in Igs.
  - - - normal human serum with its diffuse band of gamma globulins;
        
        serum from a patient with multiple myeloma producing an IgG myeloma protein;
        
        serum from a patient with Waldenström's macroglobulinemia where the cancerous clone secretes an IgM antibody;
        
        serum with an IgA myeloma protein.
- - - - W – 68,000Da
        
        Each erythrocyte contains 200-300 million molecules of Hb.
        
        Normal values: male 13.5-18.0g/100ml Female: 11.5-06g/100ml.
        
        Normal Hb types
        
        Embryonic Hb (Hb Gower 1,2, Portland), synthesized by the embryonic yolk sac.
        
        Fetal Hb (Hb F) synthesized by the fetal liver – functions very well in low O2 environment – affinity for O2 is higher that normal adult Hb.
        
        Adult Hb (Hb A; α2 β2) synthesized by bone marrow, minor form - Hb A2 (α2δ2)
        
        Glycosylated Hb- subfraction of Hb A.
  - - - This molecule returns to the mitochondria where additional reaction produces protophorphyrin IX
        
        Enzyme ferrochelates inserts iron into the ring structure producing heme.
        [Disorder of production of heme produces a variety of anaemias.
        
        A number of drugs and toxins directly inhibit heme production by interfering with the enzymes involved in heme biosynthesis. E.g lead.]
    - - 2 distinct globin chains combines to form haemoglobin.
        
        One chain- alpha, second chain – ‘non-alpha’. With the exception of the very first week of embriogenesis, one globin chain is always alpha.
        
        The fetus has one distinct non-alpha chain called gamma- 2alpha, 2 gamma - fetal hemoglobin (Hb F).
        
        Within 18-24 weeks of birth, a different non alpha-beta chain pairs with alpha, combination of two alpha and two beta chains – adult haemoglobin – Hb A
  - - - Heme is oxidised & cleaved to CO & biliverdin by heme oxigenase.
        
        Biliverdin is reduced to bilirubin by biliverdin reductase.
        
        Transport together with albumin by forming Bilirubin-albumin complex.
        
        In the liver, bilirubin is converted to diglucuronide (conjugated (reversibly combined with another) bilirubin- water soluble).
        
        Excreted into the bile --> Excretion of bilirubin into bile and later the intestines.
        
        In the intestine, bacteria de-conjugate bilirubin diglucuronide & convert the bilirubin to urobilinogens.
        
        Some urobilinogens are absorbed into the blood, transported to the kidney, oxidised to urobilin & excreted in the urine (yellowish colour). Most of it is oxidised to stercobilin & excreted via faeces (brownish).
  - - - Each individual has 4 copies of the α-globin genes (two on each chromosome 16).
        
        If one of the four genes is defective – silent carrier – no physical manifestation of the disease.
        
        If two of the 4 genes are defective – the individual is designated as having α-thalassemia trait.
        
        If three are defectives: the individual has hemoglobin H disease. Mild to moderate hemolytic anemia.
        
        If all four genes are defective: hydrops fetalis (serious edema in >2 body ares of fetus/newborns) and can results in fetal death.
    - - About 10% of RBC is destroyed by intravascular haemolysis.
        
        In circulation, the red blood cell are subjected to metabolic and mechanical stress: turbulence, endothelial damage and fibrin deposition resulting in red cell fragmentation and/or intravascular hemolysis.
        
        When RBC ruptures, haemoglobin is released into the blood.
        
        Hb dissociates into alpha-beta dimers and picked up by haptoglobin to prevent renal excretion of Hb.
        
        Haptoglobin carries the Hb to the liver for further catabolism.
      - As haptoglobin is depleted, unbound Hb dimers will appear in plasma – haemoglobinemia and are reabsorbed by kidney up to a certain level and converted to hemosiderin (iron storage complex).
        
        Intravascular hemolysis results in pink, red or brown plasma (haemoglobinemia).
        
        Beyond this level, Hb will show up in the urine – haemoglobinuria (Red coloured urine).
    - - A family of disorders caused by either production of structurally abnormal Hb molecule, synthesis of insufficient quantities of normal Hb, or rarely both.
        
        Sickle-cell anemias (HbS)
        
        Haemoglobin C disease (HbC) First two conditions – production of altered amino acid sequences.
        
        Thalassemia syndrome- decreased production of normal Hb.
    - - Occurs primarily in the US affecting 1 in 500 newborn black infants.
        
        2.1 per 100K in Malaysia per year. It is an autosomal recessive disorder in individuals who have inherited 2 mutant genes (one from each parent) that code for synthesis of mutant β-chains.
        
        The presence of this disease is not evident until sufficient HbF is replaced by HbS.
        
        Heterozygote cases- one normal and one sickle-cell gene.
        
        These individuals will have both HbS and HbA (carriers).
        
        This disease is characterised by lifelong haemolytic anemia, short of breath, extreme fatique & delayed growth in children.
        
        Also increased susceptibility to infections and other indications of poor circulation.
- - - - (tissue factor involved)
        – fibrin clot formation initiated by exposure of tissue factor (TF or factor III which binds to phospholipid, embedded deep in vessel wall) upon vascular injury.
    - - (no tissue factor/thrombin involved)
        
        fibrin clot formation initiated when contact is made between blood & exposed endothelial cell surfaces.
    - - Both pathways converge in a final common pathway involving the activation of prothrombin to thrombin and the thrombin-catalysed cleavage of fibrinogen to form the fibrin clot.
  - - - major arachidonic acid metabolite product formed by vascular cells. - potent vasodilator & inhibitors of platelet aggregation. T1/2: 3mins
    - - generated by endothelial cells, enhanced by
        many compounds, blood flow & shear stress.
    - - ASPIRIN - inhibits cyclooxygenase, hence reduce formation of TXA2
      - DIPYRIDAMOLE - reduce ADP
      - TICLOPIDINE & CLOPIDOGREL – inhibit ADP receptor.
      - THEY cause less gastric bleeding because they don’t interfere with synthesis in prostaglandins in stomach.
  - - - PLATELETS- activated by
        
        chemical reagents- ADP, epinephrine, collagen, thrombin & platelet activating factor (PAF).
        
        Immune complexes (infections).
        
        High physical shear stress.
        [Shear stress – biomechanical lateral force that is determined by blood vessel, vessel geometry and fluid viscosity]
        
        Produced from fragments of bone marrow megakaryocytes (large bone marrow cells).
        ■ Circulates 10 days in blood.
    - - VASOCONSTRICTION
        
        PLATELET ACTIVATION
        
        COAGULATION ACTIVATION
        
        Formation of fibrin mesh – entraps the platelet plug (white thrombus and/or red cells (red thrombus) forming a more stable thrombus (2nd haemostasis: minutes)
        
        Vascular injury also activates coagulation factors which subsequently interacts to form thrombin which converts soluble plasma fibrinogen to insoluble, crosslinked fibrin.
        
        This forms the secondary haemostatic plug (resistant to
        dispersal by blood flow or fibrinolysis).
        
        Partial or complete dissolution of the clot by
        plasmin
        
        Activation of blood platelets is followed by their adhesion to vessel wall at the site of injury, subsequent aggregation - build up of initial (primary) haemostatic plug. (LOOSE + TEMPORARY)
        
        Adhesion of platelets to the collagen exposed on the endothelial cell surfaces is mediated by von Willebrand’s factor (vWF produced by platelets)
        
        This plug is friable (easily crumbled) - will be washed away by local blood pressure when vasoconstriction reverses unless subsequent stabilisation by fibrin.
        
        after receptor stimulation
        
        result in:
        
        Change in platelet shape: disk to sphere with extended pseudopodia – to facilitate aggregation & coagulation activity.
        
        Release of several compounds from intracellular granules, involved in haemostasis - ADP, serotonin, TXA2 & vWF
        
        Aggregation – via membrane receptor GPIb/IX, linking by vWF & fibrinogen & exposure of another membrane receptor GPIIb/IIIa.
        
        Adhesion to vessel wall – via exposure of GPIb-IX membrane receptor through which vWF binds platelets to subendothelial collagen.
        
        trigger --> activation of platelet membrane phospholipases – hydrolyze membrane phospholipids --> releasing arachidonic acid.
        [Arachidonic acid - metabolised by cyclo-oxygenase & thromboxane synthase to --> TXA2, potent (strong, effective) but labile (easily destroyed) mediator of platelet activation & vasoconstriction]
        
        Activated plugs released --> ADP, TXA2 (activates additional platelets), serotonin (vasoconstriction), phospholipids, lipoproteins and other proteins important for coagulation cascade.
        
        temporarily reduced local blood flow - reduced blood FLOW & promote formation of platelet - FIBRIN PLUG
        
        partly mediated by 2 platelet activation products: serotonin & Thromboxane A2 (TXA2).
        
        after vascular injury- flowing blood is exposed to subendothelial tissue factor collagen-which activates extrinsic pathway.
        --> Platelets bind to collagen via von Willebrand factor(vWF).
        vWF also stimulate platelet activation.
      - Endothelial cells in the smallest blood vessels (capillaries) are supported by thin layer of connective tissue -intima (rich in collagen fibres).
        
        In veins, thin layer of contractile smooth muscle cells (media) allows venoconstriction (constriction of the vein).
        
        Due to endothelial production of two potent vasodilators & inhibitors of platelet function: prostacyclin (prostaglandin I 2,PG12) & nitric oxide.
  - - - composed of platelets and fibrins & less erythrocytes (arterial thrombus)
        • Formed at the site of injury/abnormal vessel wall particularly in areas where blood flow is rapid (arteries).
    - - primarily red cells and fibrin (venous thrombus)
        • Morphologically resembles the clot in a test tube, may form in vivo in areas of retarded blood flow/stasis with/without vascular injury or in an abnormal vessel in conjunction with an initiating platelet plug.
- - - - ABO - determines the
        “letter” of the blood.
        
        A & B = dominant, O = recessive.
        genotype --> BG - AO, AA --> A
        
        BO,BB --> B
        
        AB --> AB
        
        OO --> O
        
        determined by the antigen (agglutinogen) that are present on the surface of RBC.
        ○ Type A has antigen A
        ○ Type B has antigen B
        ○ Type O has no antigens
      - RHESUS (Rh) - determines
        the -ve or +ve of the blood.
        
        No rhesus: Rh-
        ● Rhesus present: Rh+
  - - - Our body naturally produce antibodies against AB antigens that are not present on our RBC.
        
        Like other antibodies, they are highly reactive.
        
        EG: anti-A antibody react with antigen A
        ● An antibody-antigen reaction  agglutination of RBC
        
        Antigen-Antibody Rxn
        
        This principle is used in the blood typing test.
        ● Antibodies A and B are added to blood samples.
        ● Agglutination occurs when the RBC match the antibodies.
        
        Our antibodies do not react with our own RBCs, but they will react with foreign RBCs that enter our system
        
        ABO compatibility
        
        in blood transfusion
        
        Blood transfusion is defined as a process of receiving blood products into one’s circulation intravenously. It usually involves the use of:
        ● one’s own blood
        ● or a DONOR’s blood
        
        Patients can suffer from transfusion reaction if given incompatible blood type.
        
        The recipient's antibodies will react with corresponding antigens in donor’s RBC causing a widespread agglutination.
        
        TRANSFUSION RXN
        
        occur when incompatible blood products are transfused into a patient's circulation.
        
        The destruction of incompatible RBCs is called hemolytic transfusion reaction.
        
        Reactions can occur immediately or delayed (days).
        ● Symptoms: fever, allergic rash, aching.
        
        severity depends on
        
        3 more items...
        
        For example, a type B+ recipient is not able to receive blood from A+ donor due to the presence of anti-A antibodies in the recipient.
  - - - Occur in Rh- mothers who carry Rh+ child.
        ● In 1st pregnancy, mother is exposed to Rh+ fetal blood during fetal delivery, this stimulates production of Rh antibodies in mother.
        ● In 2nd pregnancy with Rh+ fetus, Rh antibodies from mother can cross the placenta and attack fetal RBC with Rh antigens.
      - This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis).
        ● Treatment: RhoGAM® drug to prevent an Rh antibodies in mother from reacting with fetal RBC.
- - - - The blood is a mixture of cells and plasma.
        
        Cellular: RBC, WBC, platelets
        
        Plasma: pale yellow fluid that consists of water & dissolved constituent (proteins, hormones, metabolites, electrolytes, nutrients).
        
        Prepared when blood collected in specific tubes treated with anticoagulant (no clotting)
    - - Coagulation.
        
        Respiration- transport of O2 and CO2.
        
        Nutrition – transport of absorbed food materials.
        
        Excretion – transport of metabolic wastes to kidney, lungs, skin & intestines for removal.
        
        Maintenance of normal acid-base balance in the body.
        
        Regulation of water-balance through the effects of blood on the exchange of water between the circulating fluid and tissue fluid.
        
        Regulation of body temperature by the distribution of body heat.
        
        Defence against infection by white blood cells and circulating antibodies.
        
        Transport of hormones and regulation of metabolism. Transport of metabolites.