Constituents Of Blood Flashcards
Anaemia
haemoglobin level in blood below the normal level for age and sex
• male <130g/L + female <110g/L
classified according to the size of the red cells into macrocytic, normocytic and microcytic
• The Reticulocyte count, morphology of the red cells and changes in the white cell and/or platelet count help diagnose anaemia
Features of anaemia
shortness of breath on exertion, pallor of mucous membranes, malaise and angina in older people and tachycardia. Potentially also jaundice, leg ulcers
Causes of anaemia
Corpuscular (mainly haemolysis):
• membrane (eg spherocytosis, PNH)
• Haemoglobin (eg haemoglobinopathy)
• Enzymes (eg G6PD, PK)
Extra-corpuscular:
• Production mismatches- hypoplastic (not enough), dyshaemotpoeitic (ineffective production)
• Increased removal of erythrocytes- acute blood loss (haemorrhage), haemolytic anaemia, auto or alloimmune, mechanical damage, other (eg heat, chemicals)
• Deficiencies of iron, folate (macrocytic anaemia) or vitamin B12 (pernicious)
• Redistribution- hypersplenism
Classifying anaemia-hypoxia
Hypo regenerative (don’t produce red blood cells) vs hyper-regenerative (loading reed blood cells)
Reduced production vs increased destruction
Corpuscular (problem with cells) vs extra-corpuscular
Haematocrit (PCV)
ratio of volume of red blood cells to total volume (45%)
Reticulocyte
final precursor to erythrocyte. Contains some rRNA and is able to synthesis haemoglobin. Circulates in the peripheral blood for 1-2 days before maturing
Erythropoesis
regulated by the hormone erythropoietin (a heavily glycosylated polypeptide)- secreted by the kidney in response to hypoxia
• It stimulates Erythropoesis by increasing the number of progenitor cells
• Hypoxia induces synthesis of hypoxia-inducing factors (HIF-1 alpha and beta) which stimulate erythropoietin production and also new vessel formation and transferrin receptor synthesis, and reduces hepcidin synthesis, increasing iron absorption.
• Erythropoietin production increase in anaemia
Erythrocytes
120 day lifespan
• 6-8um diameter
• Anuclear biconcave disc- flexible
• Contain haemoglobin and glycolytic enzymes
• Able to generate ATP by anaerobic glycolytic pathway
• Oxygen and carbon dioxide transport
• removed in spleen, liver, bone marrow (reticuloendothelial system) and through blood loss
Haemoglobin
capable of reversibly binding to oxygen
• haemoglobin synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl co-A under the action of the rate limiting enzyme aminolavulinic acid synthase (ALA)
• Protoporphyrin combines with iron in the ferrous state to form haem
• A tetramer of 4 globin chains each with its own haem group then form to make a haemoglobin molecule
• mutations or absence of alpha or beta chains in adults referred to as thalassemia (potentially causing anaemia)
Thalassemia
mutations or absence of alpha or beta chains in adults referred to as thalassemia (potentially causing anaemia)
innate immunity
neutrophils, eosinophils, basophils, macrophages, mast cells- non-specific immunity (cytokines, phagocytosis, cytotoxicity)
Adaptive immunity
B cells, T cells- antigen-specific immunity (cytokines, antibodies, cytotoxicity)
Myelopoiesis
production of white blood cells, hormonal factor: granulocyte-macrophage colony stimulating factor (GM-CSF)- only stimulate production of myeloblastic white blood cells not lymphoid cells
Neutrophils
phagocytotic and release chemo- and cytokines to induce inflammation
Monocytes function
mature into either macrophages or dendritic cells (both antigen presenting)
Basophils
mature into mast cells.
Express surface IgE and release histamine- role in allergies an immunity (anaphylaxis)
Stain blue
Eosinophils function
Antagonistic to basophils: decrease mast cell histamine secretion
particular role in fighting parasitic infections but also wide range of regulatory functions
Where are Granulocytes produced
Made in the bone marrow under the control of a variet of growth factors and have a short lifespan in the blood stream before entering tissues
Lymphocytes
immunologically competent white cells that are involved in antibody production (B cells) and with the body’s defence against viral infection or other foreign invasion (T cells)
• Arise from haemopoietic stem cells in the marrow- T cells processes in the thymus
Only blood cells that divide
B cells
secrete antibodies specific for individual antigens (M, A, G, E, D)
20% of lymphocytes
T cells
further subdivided into helper (CD4+) and cytotoxic (CD8+) cells- they recognise peptides in HLA antigens
• Natural killer cells are cytotoxic CD8+ cells that kill target cells with low expression of HLA molecules
80% of lymphocytes
Immune response
occurs in the germinal centre of lymph node and involves B cell and T cell proliferation, somatic mutation, selection of cells by recognition of antigen on antigen-presenting cells and formation of plasma cells or memory B cells
Plasma
fluid component of blood- 55%
• Transportation medium which contains water, salt, glucose and proteins
Serum
Blood plasma without clotting factors
Cryoprecipitate
centrifuged blood plasma containing clotting factors and fibrinogen
Plasma proteins
• albumin: produced in the liver. Determines oncotic pressure of blood, keeps intravascular fluid within that space, lack of albumin leads to oedema, seen in liver disease and nephrotic syndrome ( loss of protein in urine)
• carrier proteins
• Coagulation proteins
• Immunoglobulins- produced by activates B cells
Platelets
circulate in an inactive form
• Anucleate cells- structure: plasma membrane, cytoskeleton, dense tubular system, secretory granules ( alpha, eg VWF, PF4, plasminogen; dense eg serotonine; lysosome; peroxisome)
• 2-5um
• Lifespan- 7-10 days
Where are platelets derived from
megakaryocytes- enter endomitosis where the chromosomes duplicate but the cells do not divide (polyploidy)
• Membrane blebbing process- platelets break off from the megakaryocytes. 1 megakaryocyte can produce up to 4000 platelets
• Stimulated by thrombopoietin
5 stages of platelet plug formation
- Endothelial injury
- Exposure
- Adhesion
- Activation
- Aggregation
Endothelial injury
• smooth muscle cells and nerves detect injury
• trigger reflexive contraction of vessel (vascular spasm)- reduces blood flow and loss
• Secretion of nitric oxide and prostaglandins stop- secretion of endothelin begins → further contraction
Exposure
• damage to endothelial cells exposed collagen
• Damaged cells release Von Willebrand factor (binds to collagen)
Adhesion
GP1B surface proteins on platelets bond to Von Willebrand factor
Activation
• platelet changes shape (smooth to spiculated, increasing their surface area), releases more Von Willebrand factor, serotonin, calcium, ADP, thromboxane A2 (positive feedback loop)
• ADP and thromboxane A2 result in GPIIB/IIIA expression
Aggregation
GPIIB/IIIA binds to fibrinogen and links platelets → platelet plug
3 Anti-clotting systems
- Tissue factor pathway inhibitor inhibits the tissue factor–factor VIIa complex.
- Protein C, activated by thrombin, inactivates factors VIIIa and Va.
- Antithrombin III inactivates thrombin and several other clotting factors.
Fibrinolytic system
Clots are dissolved by the fibrinolytic system.
• A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin.
• Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot.
Anti-clotting drugs
• Aspirin inhibits platelet cyclooxygenase activity thereby inhibiting prostaglandin and thromboxane production—this inhibits platelet aggregation.
• Oral anticoagulants and heparin interfere with clotting factors—they prevent clot formation.
• Recombinant tissue plasminogen activator (t-PA) is a thrombolytic—it dissolves blood clots after they are formed.
Platelet plug formation
- Injury to a vessel disrupts the endothelium and exposes the underlying connective-tissue collagen fibres.
- Platelets adhere to collagen, largely via an intermediary called von Willebrand factor (vWF), a plasma protein secreted by endothelial cells and platelets. This protein binds to exposed collagen molecules, changes its conformation, and becomes able to bind platelets- vWF forms a bridge between the damaged vessel wall and the platelets
- Binding of platelets to collagen triggers the platelets to release the contents of their secretory vesicles, which contain a variety of chemical agents. Many of these agents, including adenosine diphosphate (ADP) and serotonin, then act locally to induce multiple changes in the metabolism, shape, and surface proteins of the platelets, a process called platelet activation. Some of these changes cause new platelets to adhere to the old ones, a positive feedback phenomenon (platelet aggregation), which rapidly creates a platelet plug inside the vessel.
- Chemical agents in the platelets’ secretory vesicles are not the only stimulators of platelet activation and aggregation. Adhesion of the platelets rapidly induces them to synthesize thromboxane A2, a member of the eicosanoid family, from arachidonic acid in the platelet plasma membrane. Thromboxane A2 is released into the extracellular fluid and acts locally to further stimulate platelet aggregation and release of their secretory vesicle contents
Platelet biochemistry
Activation → adhesion → aggregation → amplification pathways
Which clotting factor is tested for as part of a prothrombin time test
Factor VII as part of extrinsic clotting pathway
Blood coagulation: clot formation:
- Blood is transformed into a solid gel when, at the site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which then bind to each other to form a mesh.
- This reaction is catalyzed by the enzyme thrombin, which also activates factor XIII, a plasma protein that stabilizes the fibrin meshwork.
- The formation of thrombin from the plasma protein prothrombin is the end result of a cascade of reactions in which an inactive plasma protein is activated and then enzymatically activates the next protein in the series.
• Thrombin exerts a positive feedback stimulation of the cascade by activating platelets and several clotting factors.
• Activated platelets, which display platelet factor and binding sites for several activated plasma factors, are essential for the cascade. - In the body, the cascade usually begins via the extrinsic clotting pathway when tissue factor forms a complex with factor VIIa. This complex activates factor X, which then catalyzes the conversion of small amounts of prothrombin to thrombin. This thrombin then recruits the intrinsic pathway by activating factor XI and factor VIII, as well as platelets, and this pathway generates large amounts of thrombin.
• The liver requires vitamin K for the normal production of prothrombin and other clotting factors.
Plasminogen
precursor for an enzyme that lyses clots
Anticlotting Systems:
- Tissue factor pathway inhibitor inhibits the tissue factor–factor VIIa complex.
- Protein C, activated by thrombin, inactivates factors VIIIa and Va.
- Antithrombin III inactivates thrombin and several other clotting factors.
• Clots are dissolved by the fibrinolytic system.
• A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin.
• Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot.
Anticlotting drugs:
• Aspirin inhibits platelet cyclooxygenase activity thereby inhibiting prostaglandin and thromboxane production—this inhibits platelet aggregation.
• Oral anticoagulants and heparin interfere with clotting factors—they prevent clot formation.
• Recombinant tissue plasminogen activator (t-PA) is a thrombolytic—it dissolves blood clots after they are formed.
Clotting screen:
• PT- prothrombin time (activity of Factor VII)
• APRT- activated partial thromboplastin time (activity of factor IX and factor XI)
• Fibrinogen
• Used to measure activity of medications eg warfarin which inhibits Factor VII, so increased PT/ heparin » elevated APRT
• Used to show haemophilia A/B/C- raised APRT without elevated PT
Constituents the coagulation cascade:
A series of proteolytic enzymes that circulate in plasma in an inactive form and generate thrombin when activated
