3. ERYTHROPOIESIS
OVERVIEW
ā£ HematopoeisisĀ describes the production of cells that circulate in the bloodstream
ā£ Specifically, erythropoiesis is the process by which red blood cells (erythrocytes)
are produced
ā£ On average, the body produces an astoundingĀ 2.5 billion red cells/kg/day
ā£ Erythrocytes arise from a complex line of cells, and their rate of production is
tightly regulated to ensure adequate but not excessive numbers of red blood
cells are produced
ā£ Learning Goal
ā£ To consider the stages and regulation of erythropoiesis,Ā and review what
happens when it goes wrong
4. ERYTHROPOIESIS
SITES OF ERYTHROPOIESIS
ā£ The site of erythropoiesis changes throughout life
ā£ In the very early foetus, it occurs in theĀ yolk sac
ā£ From 2 ā 5 monthsā gestation it occurs in theĀ liverĀ andĀ spleenĀ before finally establishing
in theĀ bone marrowĀ from about 5 monthsā gestation
ā£ In children, erythropoiesis can occur in the bone marrow of most bones
ā£ However, in adults, it only occurs in the bone marrow of theĀ vertebrae,Ā ribs, sternum,
sacrum,Ā pelvisĀ andĀ proximal femur
ā£ When erythropoiesis is inadequate in the bone marrow, this can triggerĀ extramedullary
hematopoiesisĀ ā i.e. hematopoiesis occurring outside the marrow
ā£ This is commonly seen in hemoglobulinopathies, in particular thalassemias and
myelofibrosis
5. ERYTHROPOIESIS
STAGES OF ERYTHROPOIESIS
ā£ The production of all blood cells begins with
theĀ hemocytoblast, a multipotent haematopoieticĀ stem cell
ā£ Hemocytoblasts have the greatest powers of self-renewal of any
adult cell
ā£ They are found in the bone marrow and can be mobilized into
the circulating blood when needed
ā£ Some hemocytoblasts differentiate intoĀ common myeloid
progenitor cells,Ā which go on to produce erythrocytes, as well
as mast cells, megakaryocytes and myeloblasts
7. ERYTHROPOIESIS
STAGES OF ERYTHROPOIESIS
ā£ The process by which common myeloid progenitor cells
become fully mature red blood cells involves several stages
ā£ First, they becomeĀ normoblastsĀ (aka eryhthroblasts), which
are normally present in the bone marrow only
ā£ Secondly, they lose some organelles and their nucleus as
they mature intoĀ reticulocytes, which can be thought of as
immature red blood cells
ā£ Some of these are released into the peripheral circulation
8. ERYTHROPOIESIS
STAGES OF ERYTHROPOIESIS
ā£ Finally, reticulocytes lose their remaining organelles as they mature
intoĀ erythrocytes, which are fully mature red blood cells
ā£ These normally survive for around 120 days
ā£ During this maturation process, there isĀ nuclear extrusionĀ ā i.e.
mature erythrocytes have no nucleus
ā£ Nucleated red blood cells present in a sample of bone marrow can
indicates the release of incompletely developed cells
ā£ This can occur in pathology such as thalassemia, severe anemia or
haematological malignancy
10. ERYTHROPOIESIS
REGULATION OF ERYTHROPOIESIS
ā£ Erythropoiesis is driven mainly by the hormoneĀ erythropoietinĀ (EPO), which is a
glycoprotein cytokine
ā£ EPO is secreted constantly by the kidney, at aĀ low level, sufficient for the normal
regulation of erythropoiesis
ā£ However, if the erythrocyte level becomes inadequate, the blood becomes
relativelyĀ hypoxic
ā£ When there is a reduced partial pressure of oxygen (pO2) in the kidney, this is detected
by the renalĀ interstitial peritubular cells
ā£ In response, there is a surge in EPO production, which acts in the bone marrow to
stimulate increased red blood cell production
ā£ This causes haemoglobin levels to increase, subsequently causing the pO2 to rise and
therefore EPO levels to fall so that the feedback loop is complete
19. ERYTHROPOIESIS
REVIEW QUESTIONS
ā£ What is the average lifespan of an erythrocyte?
ā£ 28 days
ā£ 40 days
ā£ 120 days
ā£ 150 days
ā£ This can be reduced in hemoglobinopathies
21. ERYTHROPOIESIS
REVIEW QUESTIONS
ā£ Which mutation is present in 95% of cases of
polycythemia rubra vera?
ā£ Philadelphia chromosome
ā£ JAK-2
ā£ Her-2
ā£ P53
ā£ This leads to dysregulation of erythropoeisis
23. ERYTHROPOIESIS
REVIEW QUESTIONS
ā£ Immature red blood cells are known as what?
ā£ Megakaryocytes
ā£ Erythrocytes
ā£ Reticulocytes
ā£ Haemocytoblasts
ā£ Reticulocytes are the direct precursor to erythrocytes
24. ERYTHROPOIESIS
REVIEW QUESTIONS
ā£ Which cell type has the greatest ability for self-renewal in
adults?
ā£ Normoblasts
ā£ Myeloblasts
ā£ Hemocytoblasts
ā£ Common myeloid progenitor
25. ERYTHROPOIESIS
REVIEW QUESTIONS
ā£ Which cell type has the greatest ability for self-renewal in
adults?
ā£ Normoblasts
ā£ Myeloblasts
ā£ Hemocytoblasts
ā£ Common myeloid progenitor
ā£ Hemocytoblasts are the precursor cell for all hematopoeisis
27. IRON METABOLISM
OVERVIEW
ā£ Iron is essential for the function of manyĀ enzymesĀ and proteins,Ā including
hemoglobin
ā£ But free iron is toxic to cells as it acts asĀ a catalystĀ in the formation of free
radicals
ā£ In order to overcome this potential toxicity,Ā complex regulatory systems
are in place to ensure the safe absorption, transportation and utilization of
iron
ā£ Learning Goal
ā£ To discuss theĀ metabolism of ironĀ in the human body, and consider the
clinical consequences when this finely balanced process is disrupted
28. IRON METABOLISM
IRON ABSORPTION
ā£ AbsorptionĀ of iron occurs in theĀ duodenumĀ and upperĀ jejunum,Ā and depends on specific
carrier mechanisms
ā£ The transporter proteinĀ Divalent Metal Transporter 1Ā (DMT1), located on theĀ apicalĀ surface
of enterocytes, facilitates uptake of non-heme ferrous iron (Fe2+) from the intestinal
lumen
ā£ Ferric ironĀ (Fe3+) in the intestinal lumen must be reduced toĀ ferrous ironĀ (Fe2+)
byĀ duodenal cytochrome B reductaseĀ (DcytB) before uptake byĀ DMT1
ā£ The iron within enterocytes can either be stored asĀ ferritin,Ā or transferred into the
bloodstream via the proteinĀ ferroportin
ā£ Once in the blood, iron is bound by the transport proteinĀ transferrin, and is mostly
transported to bone marrow forĀ erythropoiesis
ā£ Some is taken up by macrophages in theĀ reticuloendothelial systemĀ as a storage pool
29. IRON METABOLISM
IRON REGULATION
ā£ The absorption of iron is primarily regulated by a peptide
calledĀ hepcidin,Ā which is expressed by the liver
ā£ Hepcidin functions by directly binding toĀ ferroportin,
resulting in its degradation and therefore preventing iron
from leaving the cell
ā£ Hepcidin also functions by inhibitingĀ transcriptionĀ of the
DMT1 gene, so reducing iron absorption
31. IRON METABOLISM
IRON EXCRETION
ā£ It is important to note that the human body has no specific mechanism for iron excretion,
and that therefore iron levels are balanced by regulationĀ of iron absorptionĀ to match
natural losses
ā£ ApproximatelyĀ 1-2mgĀ of iron are lost from the body each day from theĀ skinĀ and
gastrointestinal mucosa
ā£ A well-balanced diet contains sufficient iron to balance this loss, as approximatelyĀ 10% of
the 10-20 mgĀ dietary iron in a balanced diet is absorbed each day
ā£ This iron can beĀ heme ironĀ from animal sources, orĀ non-heme ironĀ from whole grains, nuts,
seeds, legumes, and leafy greens
ā£ Heme ironĀ is more readily absorbed than inorganic iron which consists of both ferric
(Fe3+) andĀ ferrousĀ (Fe2+) iron
ā£ Ferric iron must first beĀ reducedĀ to theĀ ferrous formĀ before it is absorbed
32. IRON METABOLISM
IRON RECYCLING AND STORAGE
ā£ Recycling
ā£ On a daily basis, only aĀ small fractionĀ of total iron requirement is gained from the
diet
ā£ Most of the iron requirement is met from the recycling of iron within the
reticuloendothelial system, which is freed from storage and returned to the active
pool
ā£ Storage
ā£ Iron is stored in two forms,Ā ferritinĀ and its insoluble derivativeĀ hemosiderin
ā£ All cells have the ability to sequester iron as either ferritin or hemosiderin
ā£ The highest concentrations of stored iron are in the liver, spleen and bone marrow
36. IRON METABOLISM
REVIEW QUESTIONS
ā£ Where does the absorption of iron take place?
ā£ Stomach and duodenum
ā£ Duodenum and upper jejunum
ā£ Jejunum
ā£ Lower jejunum and ileum
37. IRON METABOLISM
REVIEW QUESTIONS
ā£ Where does the absorption of iron take place?
ā£ Stomach and duodenum
ā£ Duodenum and upper jejunum
ā£ Jejunum
ā£ Lower jejunum and ileum
40. IRON METABOLISM
REVIEW QUESTIONS
ā£ How is most of our bodyās iron requirement met?
ā£ A well-balanced diet
ā£ Iron supplements
ā£ Recycling of old red blood cells
ā£ Heme sources
41. IRON METABOLISM
REVIEW QUESTIONS
ā£ How is most of our bodyās iron requirement met?
ā£ A well-balanced diet
ā£ Iron supplements
ā£ Recycling of old red blood cells
ā£ Heme sources
42. IRON METABOLISM
REVIEW QUESTIONS
ā£ Which of the following contains the lowest store of iron?
ā£ Liver
ā£ Spleen
ā£ Bone marrow
ā£ Pancreas
43. IRON METABOLISM
REVIEW QUESTIONS
ā£ Which of the following contains the lowest store of iron?
ā£ Liver
ā£ Spleen
ā£ Bone marrow
ā£ Pancreas
44. IRON METABOLISM
REVIEW QUESTIONS
ā£ Which of the following does not result in iron deficiency?
ā£ Hereditary Hemochromatosis (HHC)
ā£ Vegetarian diet
ā£ Pregnancy
ā£ Excessive bleeding
45. IRON METABOLISM
REVIEW QUESTIONS
ā£ Which of the following does not result in iron deficiency?
ā£ Hereditary Hemochromatosis (HHC)
ā£ Vegetarian diet
ā£ Pregnancy
ā£ Excessive bleeding
ā£ Hemochromatosis results in iron overload, not iron
deficiency
47. MONONUCLEAR PHAGOCYTE SYSTEM
OVERVIEW
ā£ The mononuclear phagocyte system (MPS) is an important part
of the innate immune system
ā£ It serves as a network ofĀ phagocyticĀ cells in the blood and
lymphatic system as well as theĀ lymph nodes,Ā liverĀ andĀ spleen
ā£ It was previously known as theĀ reticuloendothelial system
ā£ Learning Goal
ā£ To discuss the composition and function of theĀ mononuclear
phagocyte system, and consider its clinical relevance
48. MONONUCLEAR PHAGOCYTE SYSTEM
FUNCTIONS OF THE MPS
ā£ The main role of the MPS is toĀ identify foreign antigensĀ and mount
an appropriate immune response
ā£ These antigens areĀ phagocytosedĀ before they have a chance to
cause further harm to the body
ā£ Additionally, the MPS plays a key role in the destruction of old
andĀ dysfunctionalĀ cells, which allows the body to recycle key
materials such as iron
ā£ A soluble form of stored of iron is ferritin
ā£ An insoluble form of stored of iron is hemosiderin
49. MONONUCLEAR PHAGOCYTE SYSTEM
CELLS OF THE MPS
ā£ The primary cell of the MPS is theĀ phagocyte
ā£ Phagocytes surround foreign antigens and damaged cells,
before destroying them in a process known
asĀ phagocytosis
ā£ A process which allows pathogens to be found more
easily by phagocytes is opsonisation
ā£ The most common phagocytes areĀ macrophages,
dendritic cellsĀ (derived from monocytes) andĀ granulocytes
50. MONONUCLEAR PHAGOCYTE SYSTEM
CELLS OF THE MPS
ā£ MonocytesĀ are formed in the bone marrow and circulated in the blood,
from where they migrate into surrounding tissues and further mature to
become either tissue histiocytes or macrophages
ā£ Macrophages are further categorized according to the organ they
reside in:
ā£ CNS āĀ Microglial cells
ā£ Liver āĀ Kupffer cells
ā£ Lungs āĀ Alveolar macrophages
ā£ Skin and mucosa āĀ Langerhans cells
51. MONONUCLEAR PHAGOCYTE SYSTEM
ORGANS OF THE MPS - THE SPLEEN
ā£ TheĀ spleenĀ is formed from bothĀ red pulpĀ and white pulp
ā£ The red pulp contains endothelial macrophages, which play a key role in ensuring that
defective or ageing red blood cells are phagocytosed
ā£ This allows any dysfunctional red blood cells to be disposed of, and the iron within
them can be recycled
ā£ The spleen also serves as a pool forĀ plateletsĀ andĀ red blood cells, which can be rapidly
mobilized when needed
ā£ TheĀ white pulpĀ is largely responsible for the immunological function of the spleen and,
as it is one of the organs of the lymphatic system, containsĀ B and T lymphocytesĀ too
ā£ Any antigen presenting cell passing through the spleen can stimulate activation of the
lymphocytes to mount an appropriate immunological response
53. MONONUCLEAR PHAGOCYTE SYSTEM
ORGANS OF THE MPS - THE LYMPHATIC SYSTEM
ā£ The lymphatic system consists of lymphatic vessels and
lymph nodes which act to filter tissue fluid from the blood
ā£ Lymph nodes houseĀ B and T lymphocytesĀ which detect
pathogens, leading to aĀ specific immune response
54. MONONUCLEAR PHAGOCYTE SYSTEM
ORGANS OF THE MPS - THE LIVER
ā£ The liver containsĀ Kupffer cellsĀ which reside in the vessels forming the capillary
beds of the liver, known asĀ sinusoids
ā£ As blood enters the liver via the portal vein and drains into the sinusoids, the
Kupffer cells remove foreign materials throughĀ phagocytosis
ā£ Additionally, they stimulate a local inflammatory responses usingĀ cytokinesĀ and
oxygen radicals
ā£ Kupffer cells are also involved in the metabolism of red blood cells and
hemoglobin
ā£ TheĀ hemeĀ portion is further broken down into iron for immediate reuse or for
storage, and theĀ globinĀ chains are reused
ā£ BilirubinĀ is conjugated in the liver and secreted in the bile
56. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following is a soluble store of iron?
ā£ Ferritin
ā£ Hemosiderin
ā£ Hepcidin
ā£ Transferrin
57. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following is a soluble store of iron?
ā£ Ferritin
ā£ Hemosiderin
ā£ Hepcidin
ā£ Transferrin
58. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following is an insoluble store of iron?
ā£ Ferritin
ā£ Ferroportin
ā£ Hemosiderin
ā£ Transferrin
59. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following is an insoluble store of iron?
ā£ Ferritin
ā£ Ferroportin
ā£ Hemosiderin
ā£ Transferrin
62. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ What process allows pathogens to be found more easily
by phagocytes?
ā£ Endocytosis
ā£ Exocytosis
ā£ Opsonisation
ā£ Phagocytosis
63. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ What process allows pathogens to be found more easily
by phagocytes?
ā£ Endocytosis
ā£ Exocytosis
ā£ Opsonisation
ā£ Phagocytosis
64. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ In which part of the spleen are platelets sequestered?
ā£ Gastrosplenic ligament
ā£ Malpighian corpuscles
ā£ Red pulp
ā£ White pulp
65. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ In which part of the spleen are platelets sequestered?
ā£ Gastrosplenic ligament
ā£ Malpighian corpuscles
ā£ Red pulp
ā£ White pulp
66. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following phagocytes act as the main store
for hemosiderin?
ā£ Alveolar cells
ā£ Kupffer cells
ā£ Langerhans cells
ā£ Microglial cells
67. MONONUCLEAR PHAGOCYTE SYSTEM
REVIEW QUESTIONS
ā£ Which of the following phagocytes act as the main store
for hemosiderin?
ā£ Alveolar cells
ā£ Kupffer cells
ā£ Langerhans cells
ā£ Microglial cells
69. PLATELETS
OVERVIEW
ā£ Platelets play an important role in the formation ofĀ blood clots
ā£ They are commonly described as cellular fragments ā they areĀ not true cellsĀ as
they do not contain a nucleus or carry nuclear DNA, although they do contain
mitochondria
ā£ Platelets have a life span of 7-10 days and the normal platelet count is
150-400 x 109/L
ā£ Although they are primarily found in the bloodstream, up to 30% of platelets
are transiently sequestered within theĀ spleen, ready for rapid mobilization
ā£ Learning Goal
ā£ To consider the structure, function and clinical relevance of platelets
71. PLATELETS
STRUCTURE
ā£ Platelets originate fromĀ megakaryocytes,Ā which are the largest
progenitor cells of the bone marrow and themselves originate
from theĀ common myeloid progenitor
ā£ They contain two types ofĀ granules, namelyĀ alpha-
granulesĀ andĀ denseĀ granules
ā£ Alpha-granules contain proteins of high molecular weight,
including von Willebrand Factor (vWF), factor V and fibrinogen
ā£ Conversely, dense granules contain low molecular weight
molecules such as ATP, ADP, serotonin, andĀ calcium ions
72. PLATELETS
STRUCTURE
ā£ Platelets have abundantĀ surfaceĀ receptors,Ā classified into agonist
andĀ adhesionĀ receptors
ā£ AgonistĀ receptors recognize stimulatory molecules
ā£ These include collagen, thrombin, and ADP amongst others
ā£ AdhesionĀ receptors promote the adhesion of the platelet toĀ other
platelets, the vessel wall or leucocytes, depending on the particular
receptor stimulated
ā£ Examples include the glycoprotein IIb-IIIa receptor, which is
targeted by antiplatelets such as tirafiban
74. PLATELETS
FUNCTION
ā£ The key role of platelets is their participation inĀ hemostasis
through the formation of blood clots at the site of bleeding
ā£ There are three main stages in the formation of a blood
clot:Ā
ā£ adhesion
ā£ activation
ā£ aggregation
75. PLATELETS
FUNCTION - ADHESION
ā£ Injury to the blood vessel wall exposes its underlying
endotheliumĀ andĀ collagenĀ fibres
ā£ Exposed collagen fibres bindĀ vWFĀ released from the
damaged endothelium, which in turn binds to vWF
receptors on platelets to promote adhesion
ā£ The exposed collagen itself also promotes platelet
binding
77. PLATELETS
FUNCTION - ADHESION
ā£ The exposed collagen triggers theĀ clotting cascadeĀ which, through the
utilization of tissue factors circulating in the blood, generatesĀ thrombin,Ā also
known as factor IIa
ā£ Thrombin then converts the solubleĀ fibrinogenĀ (factor I) into its insoluble
form,Ā fibrin,Ā to create a dense network of fibrin fibres
ā£ This fibrin netĀ enmeshesĀ circulating platelets to form aĀ platelet plugĀ and make a
stable clot
ā£ Factor VIII plays an important role in the intrinsic pathway, however, it is not very
stable and rapidly broken down
ā£ Von Willebrandās factor (or vWF) stabilizes factor VIII by binding to it, preventing
degradation
78. PLATELETS
FUNCTION - ACTIVATION
ā£ When a platelet binds to collagen, the glycoprotein IIb/IIIa
pathway is activated ā a complex system controlled byĀ G-
protein coupled receptorsĀ (GPCRs)
ā£ The result is the secretion ofĀ ADP andĀ thromboxane A2
which subsequently activate other platelets
ā£ Platelet activation results in a morphological change on
the membrane surface of the platelet, increasing the
surface area and preparing it for aggregation
80. PLATELETS
FUNCTION - AGGREGATION
ā£ Once activated, platelets express the GPIIb/IIIa receptor
which can then bind with vWF or fibrinogen
ā£ Fibrinogen facilitates the formation of crosslinks between
platelets, aiding platelet aggregation to form a platelet
plug
81. PLATELETS
FIBRINOLYSIS
ā£ The production of the platelet plug is an example ofĀ positive feedbackĀ and thus it is
necessary to have measures in place to prevent excessive and inappropriate clot
formation
ā£ Produced in the liver, plasminogen is activated to form plasmin by factors XIa and XIIa
ā£ Plasmin breaks down fibrin into fibrin degradation products ā commonly known as D-
dimers
ā£ It can be useful to measure the D-dimer levels in a patient where the likelihood of a
deep vein thrombosis (DVT) or pulmonary embolism (PE) is low as a negative D-dimer
excludes DVT/PE
ā£ D-dimers are non-specific to DVT/PE and can also be elevated in pregnancy, after
surgery or trauma
85. PLATELETS
REVIEW QUESTIONS
ā£ Which organ are platelets sequestered in for rapid
mobilization?
ā£ Bone marrow
ā£ Kidneys
ā£ Liver
ā£ Spleen
86. PLATELETS
REVIEW QUESTIONS
ā£ Which organ are platelets sequestered in for rapid
mobilization?
ā£ Bone marrow
ā£ Kidneys
ā£ Liver
ā£ Spleen
87. PLATELETS
REVIEW QUESTIONS
ā£ What is the main role of von Willebrandās factor?
ā£ To activate factor XII
ā£ To break down fibrinogen
ā£ To prevent degradation of factor VII
ā£ To stabilise factor VIII
88. PLATELETS
REVIEW QUESTIONS
ā£ What is the main role of von Willebrandās factor?
ā£ To activate factor XII
ā£ To break down fibrinogen
ā£ To prevent degradation of factor VII
ā£ To stabilise factor VIII
91. PLATELETS
REVIEW QUESTIONS
ā£ What is the problem in Factor V Leiden deficiency?
ā£ A mutation in Factor V
ā£ Increased levels of Factor V
ā£ Increased levels of Protein C
ā£ Reduced levels of Protein C
92. PLATELETS
REVIEW QUESTIONS
ā£ What is the problem in Factor V Leiden deficiency?
ā£ A mutation in Factor V
ā£ Increased levels of Factor V
ā£ Increased levels of Protein C
ā£ Reduced levels of Protein C
93. PLATELETS
REVIEW QUESTIONS
ā£ What is the main mechanism of action of clopidogrel?
ā£ Degradation of fibrinogen
ā£ Irreversibly inhibits cyclo-oxygenase
ā£ Prevents ADP binding to its platelet receptor
ā£ Reduces the production of thromboxane
94. PLATELETS
REVIEW QUESTIONS
ā£ What is the main mechanism of action of clopidogrel?
ā£ Degradation of fibrinogen
ā£ Irreversibly inhibits cyclo-oxygenase
ā£ Prevents ADP binding to its platelet receptor
ā£ Reduces the production of thromboxane
96. COAGULATION
OVERVIEW
ā£ Coagulation is the formation of a blood clot, and is essential
toĀ hemostasis
ā£ Hemostasis is the bodyās physiological response toĀ damaged
blood vessels, to slow down, minimize and eventually stop the
bleeding
ā£ The coagulation process is characterized by aĀ cascadeĀ of events
which lead to the formation of a blood clot
ā£ Proteins calledĀ clotting factorsĀ initiate reactions which activate
yet more clotting factors
97. COAGULATION
OVERVIEW
ā£ This process occurs viaĀ two pathways,Ā which unite
downstream to form theĀ common pathwayĀ to facilitate
hemostasis
ā£ These are:
ā£ The extrinsic pathway: This is triggered by external
trauma which causes blood to escape the circulation
ā£ The intrinsic pathway: This is triggered by internal
damage to the vessel wall
99. COAGULATION
EXTRINSIC PATHWAY
ā£ The extrinsic pathway unfolds as follows:
ā£ Damage to the blood vessel means thatĀ factor VIIĀ exits the circulation into
surrounding tissues
ā£ Tissue factor (factor III) is released by damaged cells outside the circulation
ā£ Factor VII and factor III form aĀ complex, known as the TF-VIIa complex
ā£ TF-VIIa then activates factor X into its active form, factor Xa
ā£ In conjunction with factor Va, this triggers the formation ofĀ thrombin
ā£ Note that the extrinsic pathway is believed to be responsible for the initial
generation of activated Factor X (Factor Xa), whereas the intrinsic pathway
amplifies its production
100. COAGULATION
INTRINSIC PATHWAY
ā£ The intrinsic pathway is the longer and more intricate pathway:
ā£ Factor XIIĀ is activated once it comes into contact with negatively charged
collagen on the damaged endothelium, triggering the cascade as detailed
in the previous figure
ā£ Along with clotting factors,Ā plateletsĀ form a cellular āplugā at the site of
injury
ā£ These platelets also release mediators thatĀ facilitate further clotting,
including Factor VIII
ā£ Factor IX combines with Factor VIII to form an enzyme complex that
activates factor X, which along with factor Va, stimulates the production of
thrombin
101. COAGULATION
COMMON PATHWAY
ā£ The intrinsic and extrinsic pathwaysĀ convergeĀ to give rise to the
common pathway
ā£ The activated factor X causes a set of reactions resulting in the
inactive enzyme prothrombin (also called factor II) being converted
to its active form thrombin (factor IIa) by theĀ prothrombinase
ā£ The thrombin then converts solubleĀ fibrinogenĀ (also referred to as
factor I) into insoluble fibrin strands
ā£ TheĀ fibrin strandsĀ which comprise the clot are further stabilized
byĀ factor XIII
102. COAGULATION
REGULATION
ā£ To prevent excessive clotting and subsequent disease, mediators including
Protein CĀ andĀ Protein SĀ provide negative feedback on the clotting cascade
ā£ Protein CĀ is activated following contact byĀ thrombomodulin, which is itself
activated byĀ thrombin
ā£ Along with co-factors includingĀ protein S, activated protein C degrades
factor Va and factor VIIIa, thus slowing the rate of clotting
ā£ AntithrombinĀ is a protease inhibitor that degrades thrombin, factor IXa,
factor Xa, factor XIa and factor XIIa
ā£ It is constantly active, but can be activated further by a group of common
anticoagulants known asĀ heparins
104. COAGULATION
RESTORING BLOOD FLOW āĀ FIBRINOLYSIS
ā£ In order for blood flow to be re-established as the blood vessel heals, the
thrombus must eventually beĀ degraded
ā£ During fibrinolysis, fibrin is dissolved leading to the consequent dissolution of
the clot
ā£ The endothelial cells of the blood vessel wall secrete tissue plasminogen
activators (tPAs) which convert the precursorĀ plasminogenĀ intoĀ plasmin
ā£ Plasmin subsequentlyĀ cleaves the fibrinĀ within the thrombus, leading to its
degradation
ā£ tPAs are releasedĀ very slowlyĀ following trauma from the endothelial cells, and
therefore there is aĀ substantial time delayĀ until there is a sufficient concentration
for fibrinolysis
114. COAGULATION
REVIEW QUESTIONS
ā£ What is haemophilia B?
ā£ Deficiency in factor VIII
ā£ Deficiency in factor IX
ā£ Deficiency in factor XI
ā£ Deficiency in factor XII
115. COAGULATION
REVIEW QUESTIONS
ā£ What is haemophilia B?
ā£ Deficiency in factor VIII
ā£ Deficiency in factor IX
ā£ Deficiency in factor XI
ā£ Deficiency in factor XII
119. BLOOD GROUPS
OVERVIEW
ā£ Blood typingĀ is a method of classifying blood into different
groups depending on the presence of differentĀ antigensĀ on the
surface ofĀ red blood cellsĀ (RBCs)
ā£ Understanding the different blood groups is vital in preventing
complications fromĀ blood transfusion
ā£ Learning Goal
ā£ To explore the most common blood grouping systems,
blood transfusions, associated investigations, and clinical
correlations
120. BLOOD GROUPS
ABO GROUPING SYSTEM
ā£ ErythrocytesĀ (RBCs) have multiple glycoproteinĀ antigensĀ attached to their cell
surface
ā£ The most important areĀ ABO antigens, which determine a personās ABO blood
group
ā£ An individual inherits one ABO allele from each parent, with A and B alleles
being codominant and producing the A and B antigens respectively
ā£ Group AĀ ā haveĀ A antigensĀ attached to erythrocyte cell surface
ā£ Group BĀ ā haveĀ B antigensĀ attached to erythrocyte cell surface
ā£ Group ABĀ ā haveĀ bothĀ A and B antigens attached to erythrocyte cell surface
ā£ Group OĀ ā haveĀ neitherĀ antigen attached to erythrocyte cell surface
121. BLOOD GROUPS
ABO GROUPING SYSTEM
ā£ Each person also has ABOĀ antibodiesĀ in their plasma, which will recognize and attack
RBCs expressingĀ foreign antigens
ā£ These antibodies develop over theĀ first months and years of life
ā£ This is crucial inĀ blood transfusionĀ as giving someone an incompatible blood group
can be potentially fatal
ā£ The A and B antibodies are predominantly IgM
ā£ Group AĀ ā haveĀ anti-BĀ antibodies
ā£ Group BĀ ā haveĀ anti-AĀ antibodies
ā£ Group ABĀ ā haveĀ neitherĀ antibody
ā£ Group OĀ ā haveĀ bothĀ anti-A and anti-B antibodies
123. BLOOD GROUPS
RHESUS GROUPING SYSTEM
ā£ The second most important blood grouping system is based on Rhesus
(Rh)Ā antigens
ā£ There are many different Rh antigens but only 5 are clinically significant: D, C, c,
E, and e.
ā£ Rh DĀ is the mostĀ immunogenicĀ (i.e. likely to produce an immune response) and
therefore the most likely to precipitate aĀ transfusion reaction
ā£ The presence or absence of Rh D antigen on erythrocyte cell surfaces
determines whether blood is Rhesus positive (Rh+) or Rhesus negative (Rh-)
ā£ Rh positive: have the Rh D antigen and can receive both Rh+ and Rh- blood
ā£ Rh negative: lack the Rh D antigen and should only receive Rh- blood
124. BLOOD GROUPS
RHESUS GROUPING SYSTEM
ā£ Rh negativity is generally more prevalent in Caucasian populations (15%), than
Afro-CaribbeanĀ (8%) and Asian (1%) populations but prevalence varies in
different parts of the world
ā£ Unlike ABO antibodies,Ā anti-DĀ antibodyĀ is usually not present inĀ Rh-Ā people
until they have beenĀ exposedĀ to Rh+ erythrocytes
ā£ Rh- patients shouldĀ notĀ be transfused with Rh+ blood as this can cause them to
develop anti-D antibodies, which may cause transfusion reactions in the future
ā£ Alongside ABO and Rh blood types, there are many blood group systems
based on other antigens
ā£ These antigens can also, more rarely, cause transfusion reactions
133. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What antigens are present on the RBC cell surface of
group B blood?
ā£ A antigens
ā£ B antigens
ā£ A and B antigens
ā£ No antigens
134. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What antigens are present on the RBC cell surface of
group B blood?
ā£ A antigens
ā£ B antigens
ā£ A and B antigens
ā£ No antigens
135. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What antibodies are present in the serum of group O
blood?
ā£ Anti-A antibodies
ā£ Anti-B antibodies
ā£ Anti-A and anti-B antibodies
ā£ No antibodies
136. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What antibodies are present in the serum of group O
blood?
ā£ Anti-A antibodies
ā£ Anti-B antibodies
ā£ Anti-A and anti-B antibodies
ā£ No antibodies
137. BLOOD GROUPS
REVIEW QUESTIONS
ā£ The presence of which antigens determines if blood type
will be positive or negative?
ā£ A antigen
ā£ B antigen
ā£ C antigen
ā£ D antigen
138. BLOOD GROUPS
REVIEW QUESTIONS
ā£ The presence of which antigens determines if blood type
will be positive or negative?
ā£ A antigen
ā£ B antigen
ā£ C antigen
ā£ D antigen
139. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood type can people with blood group B-positive
receive?
ā£ B-negative
ā£ AB-positive
ā£ A-positive
ā£ A-negative
140. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood type can people with blood group B-positive
receive?
ā£ B-negative
ā£ AB-positive
ā£ A-positive
ā£ A-negative
141. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood type can people with blood group O-negative
receive?
ā£ O-positive
ā£ AB-negative
ā£ AB-positive
ā£ O-negative
142. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood type can people with blood group O-negative
receive?
ā£ O-positive
ā£ AB-negative
ā£ AB-positive
ā£ O-negative
143. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood group is the universal recipient?
ā£ AB-positive
ā£ AB-negative
ā£ O-positive
ā£ O-negative
144. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What blood group is the universal recipient?
ā£ AB-positive
ā£ AB-negative
ā£ O-positive
ā£ O-negative
145. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What does the direct Coombsā test detect?
ā£ Antibodies present in the serum
ā£ Antigens attached to RBCs
ā£ Antibodies attached to RBCs
ā£ Antigens present in the serum
146. BLOOD GROUPS
REVIEW QUESTIONS
ā£ What does the direct Coombsā test detect?
ā£ Antibodies present in the serum
ā£ Antigens attached to RBCs
ā£ Antibodies attached to RBCs
ā£ Antigens present in the serum
147. References
These slide reflect a summary of the contents of
TeachMePhysiology.com and are to be used for educational
purposes only in compliance with the terms of use policy.
Specific portions referenced in this summary are as follows:
ā£ https://teachmephysiology.com/immune-system/haematology/erythropoeisis/
ā£ https://teachmephysiology.com/immune-system/haematology/iron-regulation/
ā£ https://teachmephysiology.com/immune-system/haematology/mononuclear-phagocyte-
system/
ā£ https://teachmephysiology.com/immune-system/haematology/platelets/
ā£ https://teachmephysiology.com/immune-system/haematology/coagulation/
ā£ https://teachmephysiology.com/immune-system/haematology/blood-groups/
Additional sources are referenced on the slide containing that
specific content.
