Blood Physiology Flashcards
Blood
- liquid connective tissue composed of different cells (red blood cells, white blood cells, platelets) dissolved in plasma.
- contains gases, waste products, nutrients, and hormones
- found in the circulatory system, in the blood vessels
- heavier or more viscous than water
Functions of blood (4)
- Transport of substances in blood
- Regulation of ion and pH balance
- Defense and immune protection
- Hemostasis or the prevention of blood loss
Whole blood may be separated by __________
centrifugation
- upper layer in test tube is plasma (makes 55% of blood volume)
- middle layer is called buffy coat; contains white blood cells and platelets (<1% of blood volume)
- bottom layer in test tube is red blood cells (~45% of blood volume)
Hematocrit
% of total blood volume occupied by packed red blood cells
- x/y x 100%, where x= the volume of packed red blood cells and y= total blood volume
- 42% females
- 47% males
Clinical significance of hematocrit measurement
- can indicate conditions of low numbers of red blood cells (anemia) or high numbers of red blood cells (polycythemia)
2 Major fluid compartments of the body
- Intracellular- fluid inside cells
- Extracellular- fluid outside cells (includes plasma and interstitial fluid)
Plasma
liquid portion of blood containing water, electrolytes, organic molecules, trace elements, gases
Examples of substances transported by blood
- gases oxygen and carbon dioxide
- nutrients
- waste products
- hormones
4 classes of plasma proteins
- Albumins
- Globulins
- Fibrinogen
- Transferrin
Where is the major site of synthesis of the plasma proteins?
liver
Function of albumins
- contribute to colloid osmotic pressure of plasma
- carry/transport substances in plasma
Function of globulins
- clotting factors, enzymes, antibodies, carriers for various substances in plasma
Function of fibrinogen
- forms fibrinogen threads for blood clotting
Function of transferrin
- transport of iron
3 types of blood cells
- Red blood cells (erythrocytes)
- White blood cells (leukocytes)
- Platelets (thrombocytes)
Numbers of blood cells are measured in ______ of blood
microliters
Function of red blood cells
transport of oxygen and carbon dioxide
Polymorphonuclear granulocyte white blood cells are classified according to:
- staining characteristics of cytoplasmic granules and structure of the nuclear lobes
- neutrophils, eosinophils, basophils
Function of neutrophils
phagocytes
Function of eosinophils
defense against parasites
Function of basophils
inflammation
Function of monocytes
- phagocytes and immune defense
- leave the blood stream and are transformed into tissue macrophages
2 types of lymphocytes and their functions
B cell: antibody production and humoral immunity
(Humoral immunity: immunity mediated by macromolecules found in extracellular fluids, such as antibodies, complement proteins, antimicrobial peptides. Humoral immunity involves substances found in the humors, or body fluids
T cell: cellular immunity
(Cellular immunity: immune process that involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and release of various cytokines in response to an antigen)
Hematopoiesis
- process of formation of blood cells
- before birth: yolk sac, liver, spleen
- after birth: bone marrow
- all blood cells originate from a pluripotent hematopoietic stem cell, an undifferentiated cell capable of giving rise to any type of blood cell
Cytokines
- regulate hematopoiesis
- small secreted proteins
- hormone-like as are released into blood and act on receptors on target cells
- also called hematopoietins, or growth factors that influence development of blood cells
Erythropoietin
regulates production of RBCs
Thrombopoietin
regulates production of platelets
Important characteristics of RBCs
- biconcave
- function: transport of oxygen (and carbon dioxide)
- lose nucleus and other organelles during development
- contain many hemoglobin molecules
- lifespan: 120 days
Hemoglobin (Hb)
composed of heme (non-protein) portion and globin (protein) portion
Hemoglobin A
- HbA or adult hemoglobin
- single hemoglobin molecule has 4 globin chains (2 alpha and 2 beta chains), 4 heme groups and 4 divalent iron atoms (divalent; 2+)
- each iron can bind a single oxygen; each hemoglobin can therefore bind 4 oxygen
Majority of oxygen in the body is transported in red blood cells bound to _________
hemoglobin
Hemoglobin binds oxygen in a loose and reversible manner. Why is that?
- relaxed binding structure of hemoglobin allows oxygen to bind in a cooperative manner, meaning the binding of successive oxygen molecules facilitates or helps the binding of the next oxygen
Oxyhaemoglobin
- is hemoglobin to which oxygen is bound; it has a relaxed binding structure
Deoxyhemoglobin
- has a tight binding structure and has given up oxygen
Oxygenation
- the process by which a ferrous iron combines with one molecule of oxygen
What makes CO inhalation fatal?
- Hb can bind oxygen, carbon dioxide, nitric oxide and carbon monoxide
- Hb has a higher affinity for carbon monoxide (200x higher) than for oxygen, meaning it prefers to bind carbon dioxide and does so very tightly, which makes it difficult to remove from the Hb
- carbon monoxide is colorless, odorless and has high affinity for Hb, making it fatal as Hb cannot bind oxygen and deliver it to the body
3 different factors essential for RBC production
- Cytokines- erythropoietin (EPO) stimulates RBC production
- Dietary factors- iron needed in Hb, folic acid, and vitamin B12
- Intrinsic factor- made by cells in the stomach and needed for absorption of vitamin B12
Erythropoietin (EPO)
cytokine, stimulates RBC synthesis
What is the stimulus for EPO secretion from the kidneys?
decreased oxygen delivery to the kidneys
EPO acts on __________________ to increase product of RBC
bone marrow hematopoietic stem cells
What happens next when there is decrease in tissue oxygenation
- Decrease in tissue oxygenation
- Stimulates release of EPO production from kidneys
- Stimulates hematopoietic stem cells in bone marrow
- Increases production of RBC by bone marrow
- Increases oxygen-carrying capacity of blood
- Increase tissue oxygenation
Hypoxia
- low oxygen concentration in the blood
Factors contributing to hypoxia
- low blood volume
- anemia
- low hemoglobin
- poor blood flow
- pulmonary disease
- basically, any factor that reduces the ability of blood to carry oxygen (low blood volume, anemia, low hemoglobin), that affects delivery of oxygen to tissues (low blood volume and flow) and affects ability to take in oxygen (pulmonary disease)
Iron
- needed for production of RBC
- obtained from food and absorbed into blood in intestine
- transported in blood bound to transferrin (iron transport protein)
- used in bone marrow to make RBC
Body iron reserve
50% iron is from Hb from dying RBC
25% stored in other iron-containing proteins
25% stored in liver bound to ferritin (a protein)
Old or damaged RBC taken up by macrophages in spleen by ____________
phagocytosis
Hemoglobin is broken down into
heme and globin
Heme is broken down into
iron and biliverdin
Iron- absorbed into blood for erythropoiesis or stored in spleen or liver bound to ferritin
Biliverdin-> converted to bilirubin -> secreted into bile and enters small intestine
Globin is broken down into
amino acids
Vitamin B12
- required for normal production of RBC
- obtained from diet
- absorption from GI tract requires intrinsic factor (a protein), secreted by cells in stomach wall
- vitamin B12 and IF form a complex to allow vitamin B12 to be absorbed
Pernicious anemia
due to lack of vitamin B12 or intrinsic factor
Anemia
- decreased oxygen-carrying capacity of the blood due to a deficiency of RBCs and/or hemoglobin contained in the RBCs
- lack of iron
- abnormal structure of hemoglobin
Aplastic anemia
- damage of bone marrow due to radiation/drugs
Chronic kidney disease
- reduced level of erythropoietin (EPO)
Hemolytic anemia
- increased breakdown due to abnormal shape of RBC or due to immune reactions during transfusion
Hemorrhagic anemia
- increased blood loss due to injury, bleeding ulcers or chronic menstruation
Normal adult hemoglobin
HbA (2 alpha and 2 beta chains)
Sickle cell disease
- have abnormal Hb called HbS
- sickle-shaped RBC with hard, nonflexible cell membranes
- RBC in sickle cell disease are damaged as they pass through capillaries and this leads to hemolytic anemia
- an autosomal recessive disease (the gene for Hb S has to be inherited form both parents)
Immunity
- refers to process that help a cell or the interior of our body defend against anything foreign- it protects our ‘self’ from our ‘non-self’
2 types of immunity
- Innate/natural immunity
- Acquired/adaptive/specific immunity
Innate/natural immunity
- immunity we are born with
- includes non-specific defenses in the body such as physico-chemical barriers, or physiological and chemical barriers of the body (skin, enzymes in body fluids, acid secretion in stomach, WBCs)
Acquired/adaptive/specific immunity
- acquired over time and upon exposure to foreign pathogens/cells
- foreign object triggers the immunity to develop
- WBC important
WBC
- produced from pluripotent stem cells in bone marrow
- pluripotent cells converted to: granulocytes (neutrophils/eosinophils/basophils), monocytes or lymphocytes (B cells and T cells)
Lymphocytes
- production begins in bone marrow
- migrate to thymus to complete development then return to blood
- may migrate to peripheral tissues and are returned to circulation by lymphatic system
Differences between innate/natural immunity and acquired/adaptive immunity
Key features:
- Innate: non-specific, no memory, fast (sec/min/h)
- Adaptive: specific, has memory, slow (days/weeks)
Major cells involved:
- Innate: phagocytes (neutrophils and macrophages)
- Adaptive: Lymphocytes (B and T cells)
Major molecules involved:
- Innate: complement system
- Adaptive: antibodies, cytotoxic molecules
Appropriate responses of the immune system
defense, remove old/damaged/abnormal cells
Inappropriate responses of the immune system
allergies, autoimmune reactions
Inflammation
- the non-specific innate immune response to tissue injury initiates inflammation; part of body’s immune response
Purpose of inflammation
To cause healing and resolve injury, destruction of non-self agents and formation of scar tissue (fibrosis)
Physical characteristics of inflammation
- redness
-swelling - heat
- pain
- loss of function
Changes in vasculature following injury
- release of inflammatory mediators (histamine)
- histamine causes vasodilation of blood vessels, which increases blood flow causing the redness and heat of inflammation
- histamine causes blood vessels to become leaky or more permeable, allowing proteins and fluid to move to the extracellular space. The fluid causes the swelling of inflammation
2 major components of acute short term inflammation
- Vascular events -refers to events involving blood vessels
-release of histamine
-local blood vessels dilate
-local blood vessels become leaky
-accumulation of protein and fluid in the extracellular space
-inflammatory mediators are released: bradykinin, prostaglandins, complement proteins - Cellular events -refers to events associated with cells
-resident macrophages entrap and kill pathogens, release chemical signals
-increased movement of WBCs (neutrophils and monocytes) into infected area
-phagocytosis and destruction of foreign agent
Cellular events associated with inflammation (8)
- cellular events of inflammation act to bring WBCs to the inflamed tissue and kill the “non-self” agent
- Margination of WBCs- move to edge of blood vessels
- Tethering and rolling of WBCs inside blood vessel -attaching of WBC to endothelial cells of the blood vessels and slow rolling along the vessel
- Activation of WBCs and endothelial cells -involves expression of proteins on the surface of neutrophils and endothelial cells
- Arrest/firm attachment of WBCs to endothelial cells -neutrophils bind to complementary proteins on endothelial cells and stop rolling
- Emigration/ diapedesis -white blood cells squeeze in between adjacent endothelial cells to exit out of the blood vessel and move into the tissue spaces
- Chemotaxis of WBCs - WBCs move toward the site of inflammation by chemotaxis, a process of cell movement that occurs in response to specific molecules or chemical attractants
- Recognition of “non-self” by WBCs -at the site of infection, WBCs recognize foreign agents by recognizing chemical molecules on their surface
- Phagocytosis of “non-self” pathogen by WBCs -process by which foreign pathogens or bacteria are engulfed by neutrophils
Chemotaxis
- the ability of WBCs to move against a concentration gradient (low -> high concentration) in response to chemical factors; they move towards the source of a chemotactic substance
Chemotactic factors (chemo-attractants)
chemical factors that attract WBCs to the site of inflammation
Phagocyte
a cell that can eat other non-self pathogens or dying cells by engulfing them with temporary cytoplasm filled extension of the plasma membrane (pseudopodia)
examples of phagocytic cells: monocytes, macrophages, dendritic cells and neutrophils
Steps involved in phagocytosis (6)
- Recognition of substance to be ingested -macrophages have cell-surface receptors that recognize certain molecules on the surface of various pathogens
- Attachment of phagocyte to the substance to be ingested -this activated the process of phagocytosis
- Pseudopodia reach around substance and come together to form a phagosome inside the phagocytic cell
- Fusion of the phagosome to a lysosome to form phagolysosome
- Destruction of ingested substance by lysosomal enzymes
- Release of end products into the cell or out of the cell by exocytosis
Phagocytic cells, like macrophages, have receptors called ________________, or _______________
pattern recognition receptors, or toll-like receptors
Receptors recognize a specific pattern of molecules expressed on bacteria, and therefore do not have to recognize a specific bacteria
Opsonins
- molecules added to the surface of a bacteria to help in speeding up the rate of phagocytosis by macrophages or other phagocytic cells
- produced by self or host body
- opsonins may eb antibodies or complement-type proteins
Opsonization
- coating of the bacteria with opsonins (either antibodies or complement-type proteins) produced by the host body which then facilitates the attachment and phagocytosis of the bacteria by the phagocytic cell
Neutrophils
- important in immune response
- kill bacteria by: oxygen-dependent process or oxygen-independent process
Oxygen-dependent killing
corrosive oxygen free radical products are synthesized to destroy a foreign body
Oxygen-independent killing
use different bactericidal enzymes
Lysozymes- enzymes which work inside phagolysosomes to degrade entire bacteria by proteolytic breakdown
Lactoferrin- binds to iron and reduces iron in the environment so that bacteria cannot grow
Defensins- drill holes on the surface of a bacteria
Complement proteins
- found inactive in plasma
- activated by a cascade or step-wise activation process which amplifies the signal
- involved in the innate immune response
Function of Activated complement proteins
(OIL)
- Opsonization; activated complement proteins act as opsonins, which lead to potentiated phagocytosis
- Inflammation mediator; activated complement proteins act as chemoattractants, attracting other immune cells to the site of inflammation, increasing vascular permeability and histamine release from mast cells
- Lysis; complement proteins cause lysis of bacteria
Killing by MAC formation (lysis)
- Activated complement proteins may kill a pathogen by forming a membrane attack complex or MAC
- The activated complement proteins come together and form a pore on the surface of the bacteria
-Involves complement proteins, therefore part of the innate immune response
B and T lymphocyte/cell development starts in the _____________
Bone marrow
This lymphocyte remain in bone marrow for development
B lymphocytes
This lymphocyte leave bone marrow during development and move to thymus gland to complete development
T lymphocytes
Both B and T lymphocytes move to the _____________ once developed
Blood circulation
The ______________ and the ________ are primary lymphoid tissues
Bone marrow and thymus
These are sites where B and T lymphocytes are developed but they are not exposed to foreign pathogens or antigens
Peripheral lymphoid tissues or nodes
- B and T lymphocytes move to peripheral lymphoid tissues or nodes
- This is where lymphocytes come in contact with foreign antigens and fully mature
- Peripheral lymph nodes or tissues are called secondary lymphoid tissues
- Activated lymphocytes can move back to the blood circulation through the lymphatic circulation
Roles of B and T lymphocytes in acquired immunity (3 R’s)
- Recognize a specific foreign antigen or agent
- Respond to the antigen by mounting an immune response to bring about their destruction
- Remember the first encounter with the antigen (important feature of acquired immunity)
Antigens
Molecules that are specifically recognized by an antibody to form an antigen-antibody complex
Antibody
- belongs to the globulin class of plasma proteins (Immunoglobulin class)
- Y shaped molecule with two heavy chains and two light chains. The light and heavy chains are connected to each other by disulfide bridges
- The site formed by the combination of light and heavy chains on both arms of the Y-shaped molecule forms the highly specific binding site of the antibody (ie. This is where the antigen binds)
Humoral immunity
- the aspect of immunity mediated by macromolecules such as secreted free-circulating antibodies found in the humors, or body fluids
- developed when naive B cells in the lymph nodes are exposed to foreign antigens
- B cell binds a complementary antigen and then undergoes mitosis, or clonal expansion
Clonal expansion
- In clonal expansion, all progeny carry the same antigen specificity
- During antigen-specific clonal expansion, two groups of B cells are formed
- Once group differentiates into short-lived plasma cells
- Other group retains the specific receptor for the foreign antigen and circulates in the plasma as memory cells
- The antibody-like molecules on he surface of the B cells act as a receptor to recognize a specific antigen
Plasma cells
Synthesize antibodies specific to the foreign antigen that initiated the clonal expansion. The free antibody molecules contribute to humoral immunity and are known as free circulating antibodies
Memory cells
Long-lived cells which retain the memory of the first exposure for many years to come
Free circulating antibody molecules bind specific foreign antigens to form antigen-antibody or immune complexes
What are the functions?
- Direct effect of antibodies: antibodies can neutralize toxic molecules produced by bacteria
- Indirect effect: involves use of the antibody as an opsonin or for the purpose of complement activation
-Once complement proteins are activated, the effects of OIL could set in (Opsonization, inflammation mediator, and lysis)
Acquired immunity has a cell-mediated component
- Cellular immunity is an immune response that does not involve antibodies, but rather activation of phagocytes, T cells and the release of various cytokines
- Cellular immunity:
-virus infections, cancer cells and transplanted organs
-involves T cells: cytotoxic T cells, helper T cells and memory T cells - T cells perform the three R’s
-recognize a specific foreign antigen
-respond to a foreign antigen by generating a cellular immune response
-remember the first encounter with a foreign antigen
Unique feature of the T cell mediated immune response
T cells require the foreign antigen to be presented in a unique manner known as “antigen presentation”
Antigen presentation
- T cells require the foreign antigen to be presented in a unique manner
- a process whereby a host cell, such as a macrophage or a dendritic cell, engulfs the foreign protein, or antigen and presents it to the T cell complexed with the host’s proteins
- antigen is taken up by a macrophage and processed into smaller pieces by the macrophage’s enzymes. The small pieces of the foreign protein are then loaded on to a specific intracellular protein called MHC (major histocompatibility complex protein). The small pieces of the antigen are then presented on the surface of the antigen presenting cell to a naive T cell
MHC proteins are coded for by ______ genes
MHC
Two types of MHC proteins and their definition
- MHC I: found virtually all nucleated cells
- MHC II: found specifically in antigen-presenting cells such as macrophages and dendritic cells
How does a bacterial infection lead to antibody synthesis in secondary lymphoid tissue?
Steps for the development of acquired immunity:
- Following a cut or break in the skin, bacteria invade the host body and are transferred through blood or a lymphatic vessels into a lymph node
- The bacterium can be be recognized specifically by B cells which then undergo clonal expansion to form plasma cells and memory B cells. The plasma cells can produce free circulating antibodies. These antibodies are specific to the foreign antigen.
(B cells -> clonal expansion -> antibodies specific to the foreign antigen) - In the lymph node, a macrophage or dendritic cell can engulf the same bacterium, and present the foreign antigen to a helper T cell. The helper T cells can proliferate to become activated helper T cells. These activated T cells can produce cytokines which can interact with the B cells that undergo clonal expansion.
(Macrophage -> antigen presentation -> activated T cells make cytokines which interact with the B cells)
Interaction of B cells and T cells in acquired immune response
During B cell-mediated development of immunity, T cells interact to provide help via production of cytokines
Immunological Memory
- antigen is injected and the host body produces antibody
- immunological memory is an important feature of acquired immunity
-The first or primary response -> slow to develop and the amount of antibody generated is not large
-The host body remembers the first encounter to the antigen and if exposed to the same antigen again, the host responds in a fast and quick manner which is known as the secondary response
-Secondary immune response -> antigen A is injected a second time and the magnitude of the response is large and very quick - this feature of memory is effectively used for vaccination purposes to provide immunity against diseases
Active immunity
- direct exposure to the antigen or exposure by vaccination
- the antibodies are self-generated
- the immunity is not immediate -days to weeks
- duration of the immunity: months to years
- combat future infection
Passive immunity
- occurs when pre-formed antibodies are transferred from a mother to the fetus during pregnancy or by nursing in the postnatal stage
- does not take time to acquire (immediate)
- duration of the immunity: short-lived
- provides help for the child until their own immune system is fully developed
Hemostasis
- the prevention of blood loss
- platelets are important in hemostasis = found in the middle “buffy coat” mixed with the white blood cells
Why is Hemostasis necessary? (3)
- Pro-hemostatic factors prevent blood loss
- Anti-hemostatic factors are factors which keep the blood fluid
- Our body tries to maintain a state where blood can circulate smoothly, without formation of unnecessary clots
Key Steps of Hemostasis (3)
- Vasoconstriction (vascular spasm)
- A ruptured blood vessel contracts to minimize blood loss at the site of the cut - Primary hemostasis or platelet plug formation
- Platelets aggregate to form a platelet plug or a white thrombus (it is known as white thrombus because platelets are colorless plugs) - Secondary hemostasis or blood clotting/coagulation (red thrombus)
- If the bleeding does not stop after the formation of the white thrombus, blood clotting enzymes are activated to form a stronger gel-like clot at the cut site. This is known as red thrombus as it is reddish in color
Factors which trigger vasoconstriction (3)
- An injury stimulates pain receptors that activate nerve endings that are directly affected by the cuts, causing vasoconstriction
- Injury to blood vessel smooth muscle, causing vasoconstriction
- Local injury to the platelets causes the release of serotonin, which acts as a vasoconstrictor
The word thrombus refers to a __________
blood clot
Platelets=__________
thrombocytes
Where do platelets come from?
- Platelets originate from the pluripotent stem cells of the bone marrow
- Pluripotent stem cells are converted to cells called megakaryocytes
Structure of platelets
- Platelets contain organelles such as vesicles called alpha granules and dense granules. Do not contain a nucleus
- Contain glycogen for energy
- Contain contractile proteins actin and myosin
- Contain surface glycoproteins which act as receptors
- Contain canaliculi
Contents of alpha granules
Alpha granules contain large molecules:
- Adhesive protein von Willebrand factor
- growth factors
- some blood clotting factors
- cytokines
Contents of dense granules
Dense granules contain small molecules
- ADP
- ATP
- 5-hydroxyptamine (serotonin)
- Calcium
Platelet plug formation (primary hemostasis) (3)
- Adhesion
- platelets must adhere to a surface in the process of hemostasis
- normally do not stick to the smooth surface of blood vessels but an injury to blood vessels disrupts the endothelial layer and exposes the underlying collagen
- platelets adhere to the collagen tissue using von Willebrand factor - Activation of platelets:
- binding of platelets to collagen triggers the release of chemicals from their storage granules (ADP and serotonin)
- ADP and serotonin act locally on the platelets to change metabolism, shape, and expression of receptors on the surface of the platelet - Aggregation of platelets
- new platelets to adhere to old ones by a positive feedback effect which rapidly forms a platelet plug inside the vessel
von Willebrand factor
- is a protein secreted by platelets and endothelial cells
- once secreted, von Willebrand factor can change conformation and bind to platelets
- von Willebrand factor forms a bridge between the damaged vessel wall and the platelets
Once the von Willebrand factor forms the bridge between the damaged vessel wall and platelets, the platelets become activated. What happens after this?
- The activated platelets express a fibrinogen receptor on their surface, which can bind to fibrinogen, a plasma protein, and other platelets to form a network, or lattice-like structure, which ultimately forms the plug.
- During this process the activated platelets also secrete thromboxane A2 and ADP, which attract more platelets to the cut site, and the aggregation continues
What happens after the platelet plug is formed?
- After the plug is formed, the plug can contract using its contractile proteins actin and myosin to tighten the plug and seal the cut site
Adhesion of platelets triggers activation of the _________
platelets
Once platelets are activated, they secrete the compounds:
What do they do?
- Serotonin (5HT) and ADP
Serotonin acts a s a vasoconstrictor
ADP plays a role in further platelet aggregation - Thromboxane A2: promotes further platelet aggregation and vasoconstriction of the vascular smooth muscle which will reduce blood flow to the cut site
- Upon platelet activation, phospholipids exposed on the surface of the platelet aid in the conversion of prothrombin to thrombin, which acts to promote further platelet aggregation
Why does the plug not expand along the undamaged endothelium of the blood vessel?
Adjacent undamaged endothelial cells synthesize and release prostacyclin, and nitric oxide which inhibit the spread of the platelet plug along undamaged endothelium
Role of Prostacyclin (prostaglandin I2 or PGI2)
inhibits platelet aggregation
Role of Nitric oxide (NO)
inhibits platelet adhesion, activation and aggregation
The innate response of inflammation occurs within seconds of the initiation of injury. Following some time lag, chemicals are released from the _______________ which start the process of healing by initiating the formation of the platelet plug at the site of the cut
blood vessel wall
Membrane damage, or a disturbance in the cell membrane, initiates the production of __________________ from membrane phospholipids
arachidonic acid
What happens to arachidonic acid in the lipoxygenase pathway
Arachidonic acid is converted to leukotrienes by the enzyme lipoxygenase, and these chemicals then initiate inflammatory responses of swelling
What happens to arachidonic acid in the cyclooxygenase pathway
- Arachidonic acid is converted to a prostaglandin by an enzyme known as cyclooxygenase or COX
- Platelets and endothelial cells both have the cyclooxygenase enzyme, but they have different isoforms, or variants, of the enzyme. As a result, the hemostatic responses will vary. The prostaglandins play a role in hemostatic effects that help to prevent blood loss
Generally, the acute inflammatory response precedes _______________
hemostatic effects
Aspirin
- is prescribed to prevent clot formation in patients that have a potential risk for heart attacks
- can inhibit the actions of both COX-1 and COX-2
Two isoforms of the cyclooxygenase enzyme
COX 1 and COX 2
The cyclooxygenase pathway in healthy endothelial cells is subject to the action of this enzyme
COX 2 enzyme
COX 2 activity results in
- results in the synthesis of prostacyclin and this has an anti-hemostatic effect.
- The prostacyclin synthesized from arachidonic acid keeps the plug from expanding to adjacent undamaged endothelial cells
The cyclooxygenase pathway in platelets is subject to the action of this enzyme
COX 1 enzyme
COX 1
- produces thromboxane A2 and has a pro-hemostatic effect, or favors the formation of a platelet plug
What happens once COX 1 is inhibited by aspirin in the platelets?
- the chances of producing thromboxane A2 are completely blocked.
- platelets are non-nucleated cells and once their enzyme is inhibited, the actions of COX 1 enzyme are completely blocked, as they cannot synthesize new COX 1 enzyme
What happens once COX 2 is inhibited by aspirin?
- healthy endothelial cells will eventually start synthesizing new COX-2 enzymes as they are nucleated.
- COX 2 enzymes then convert arachidonic acid to prostacyclin
Aspirin can block the ________ pathway only and block all the pro-hemostatic pathways. ________ pathways can overcome the inhibition of aspirin to make prostacyclin and keep the vessels vasodilated and decrease platelet aggregation
COX 1
COX 2
Low dose aspirin is used in patients who
may have an increased risk of heart attacks to prevent clot formation
Blood clotting
- a process by which blood is transformed into a solid gel called a clot, or thrombus, and consists of a protein called fibrin.
The essential part of a clot is the formation of ________
fibrin
Secondary hemostasis
- occurs following a platelet plug formation
- involves a cascade of enzyme (clotting factors) activation
- activation of enzymes occur by proteolytic cleavage
- formation of gel-like fibrin clot, in which red blood cells become trapped and is called a red thrombus
How many factors are involved in blood clotting?
13
Factor IV
- is ionized calcium (is not a protein)
Many of the activation reactions take place on the surface of ______________
platelets
Where are the factors (involved in blood clotting) synthesized?
liver
What are the 4 most important factors involved in the key steps of clotting?
(their number and names)
- Factor I =fibrinogen
- Factor II =prothrombin
- Factor III =tissue thromboplastin
- Factor IV =calcium
What is the key step in the clot formation pathway?
Generation of the active thrombin enzyme
An inactive enzyme prothrombin is converted to thrombin by the ________________
prothrombinase complex
Thrombin
- the active enzyme which converts the inactive protein fibrinogen to the active form fibrin
Fibrin
- is an insoluble protein which upon stabilization becomes strong strands and forms a mesh-work, or the fibrin clot, in which cells get trapped
Factor Xa
- is directly involved in the formation of active thrombin
Two pathways by which clotting factors are activated to form a common activated factor, which is called Xa
- Intrinsic pathway- all factors come from within the blood and the blood vessel itself
- Extrinsic pathway- is initiated by some factors outside the blood vessel
Both pathways meet and activate the common factor in the common pathway leading to the formation of a blood clot
Intrinsic and extrinsic pathway merge at the formation of ___________ and lead to the formation of ____________ in the common pathway
active factor X
active thrombin
Everything necessary in this pathway is found in the blood
Intrinsic pathway
In this pathway, a cellular element outside the blood is needed
Extrinsic pathway
Intrinsic pathway begins with the activation of __________, which becomes activated when it comes into contact with the surface of a damaged blood vessel wall, to form _______
factor XII
XIIa
Factor XII is known as “____________________”
contact activation factor
In the case of blood collection, the rough inner surface of the test tube resembles a damaged blood vessel wall, which activates ________, and hence triggers clotting.
If the glass tube is coated with silicone, the inner surface becomes smooth and blood does not clot in vitro
factor XII
When is the extrinsic pathway activated?
- It is activated when factor VII come sin contact with tissue products and tissue factors outside a blood vessel
Where are tissue factors located?
- Tissue factors are located on the outer plasma membrane of various tissue cells or cells in the walls of blood vessels outside the endothelium. The blood is exposed to these subendothelial cells when the vessel is damaged and the endothelial lining is disrupted
In the presence of phospholipids exposed on activated platelets and calcium, factor _____ is activated by binding to tissue factor. Factor _____ then activates factor ___, to produce _______
VII
VIIa
X
activated factor X or factor Xa
Activation of factor X then leads to
- leads to the common pathway of fibrin formation
Physiological Pathway of Blood Clotting
- Clotting is initiated in the extrinsic pathway when factor VII is activated in the presence of tissue factors which are exposed when a cut occurs and are found immediately outside the cut site
- Factor VIIa then produces a small amount of active factor Xa, which activates a small amount of fibrin. The amount of thrombin produced form the extrinsic pathway is too small to produce adequate sustained coagulation
- This initial amount of thrombin provides a powerful feedback effect to many of the factors of the intrinsic pathway , including factors V, VIII and XI and factor XIII. This positive feedback effect of thrombin initiates the further formation of thrombin, thereby stimulating its own formation. This activated intrinsic pathway produces a large amount of thrombin, and produces a large fibrin clot.
The pathways are activated sequentially with _____ being the link between them
thrombin
A deficiency in factor VII causes
serious bleeding
Individuals that lack factor VIII experience
severe bleeding and are known as hemophiliacs
Lack of factor IX causes
moderate bleeding
A lack of factor XII causes
no bleeding problem in vivo, but blood doe snot clot in the glass test tube in vitro
Clotting is not initiated by factor XII
Blood form a healthy individual will clot when placed in a glass test tube with no ______________
anticoagulant
- When the blood touches the glass, factor XII is activated and initiates clot formation in the glass test tube
- When the glass is coated by silicon, the surface of the glass becomes too smooth to trigger the activation of factor XII. hence factor XII does not initiate the intrinsic pathway
What does Thrombin do in the clotting pathway?
- activation of platelets
- converts soluble fibrinogen into insoluble fibrin
- activates several other clotting factors, including factor V, VIII, XI and XIII
- plays a role in anti-clotting pathways (anti-coagulant activity)
Anticoagulants
prevent clot formation where and when it is not required
Fibrinolysis
the enzymatic breakdown of the fibrin in blood clots
What are 3 natural anticoagulants in our body
- TFPI or tissue factory pathway inhibitor
- Antithrombin 3
- Thrombomodulin
TFPI or tissue factory pathway inhibitor
- inhibits tissue factor, or factor III, that is involved in the activation of factor VII
Tissue factor (factor III)
- initiates the extrinsic pathway of clotting as it is needed to activate factor VII, which activates factor X
Antithrombin 3
inhibits the actions of thrombin
Thrombomodulin
- a protein expressed on the surface of undamaged, healthy endothelial cells
- binds to thrombin to prevent formation of a clot
Bound thrombin activates inactive _______ to form active ________
protein C, protein C
Protein C then interacts with protein S, and they inhibit factors Va and factor VIIIa
Factor Va
- involved in the formation of thrombin
Factor VIIIa
- closely involved in the formation of factor Xa
Actions of thrombin as an anticoagulant
Healthy endothelial cells express thrombomodulin
- Thrombomodulin binds to thrombin and activates protein C
- Activated protein C inhibits factors VIIIa and Va
Calcium chelators such as ___________, bind ionized calcium, removing the free ionized calcium, and preventing the activation of clotting factors in the clotting pathways
sodium citrate
Heparin increases the activity of _________
antithrombin 3
Vitamin K antagonists inhibit the synthesis of certain clotting factors that are dependent on vitamin K in the clotting pathway. What are these clotting factors
Factors II, VII, IX and X
This is a plasminogen activator. It converts inactive plasminogen to the enzyme plasmin. The plasmin then breaks down the insoluble fibrin strands into soluble fibrin degradation products to dissolve the clot
tPA, or tissue plasminogen activator
tissue plasminogen activator (tPA) is released from ______________________
healthy endothelial cells
Clinical clot busters or thrombolytic drugs
- used to treat patients with heart attacks to dissolve clots
- thrombolytics work by dissolving a major clot quickly to restart blood flow to the heart and helps prevent damage to the heart muscle
Abnormal hemostasis is the imbalance of _____________ and ________________
PRO- and ANTI-hemostatic factors
What happens when pro-hemostatic factors fail?
- severe bleeding disorders which lead to hemorrhage may occur
- defects in pro-hemostatic pathways
Defects in pro-hemostatic pathways may include:
problems with the platelets:
- Thrombocytopenia- a deficiency in the numbers of platelets
- Abnormal platelet function due to a deficiency of von Willebrand’s factor (the plasma protein secreted by endothelial cells and platelets that promotes adhesion by binding to platelets and exposed collagen molecules in damaged blood vessels)
problems with clotting factors
- hereditary deficiencies of clotting factors
- a number of clotting factors require vitamin K for their synthesis and a lack of vitamin K may cause a deficiencies of these factors
What happens when anti-hemostatic factors fail?
- blood clots remain in the circulation for a long time leading to thrombosis (formation of blood clot in the vessel, blocking blood flow)
- deficiencies of natural anticoagulants and fibrinolytic factors due to hereditary disorders may cause thrombosis
- acquired disorders, such as decreased blood flow, may also lead to the formation of blood clots
Blood types are based on
the antigens carried on the surface of red blood cells
The different blood types in the ABO system are:
Group A, B, AB and O
The ABO class of antigens are ___________ molecules
carbohydrate
Blood group A
has antigen type A on the surface of the red blood cells
anti-B antibodies
Blood group B
has antigen B on the surface of the red blood cells
anti-A antibodies
Blood group AB
has both antigens A and B on the surface of the red blood cells
no anti-A or anti-B antibodies
Blood group O
has no surface antigens of the ABO type on the surface of the red blood cells
both anti-A and anti-B antibodies
_____________ are found on surface of red blood cells while _____________ are found in blood
antigens, antibodies
ABO system, red blood cell surface antigens are _____________, not proteins
carbohydrates
A person with blood type A carries gene A, but gene A does not directly code for the surface antigen A because it is a carbohydrate molecule.
What does gene A do instead?
Gene A instead codes for the specific enzyme A that allows the attachment of the carbohydrate antigen A to protein molecules expressed on the surface of red blood cells
______ genes code for enzymes (proteins) of the ABO system
ABO
The genes __ and ___ are dominant over O in heterozygous individuals
A and B
Blood type A can be homozygous ____ or a heterozygous ___
AA
AO
Blood type B can be homozygous ___ or a heterozygous ___
BB
BO
Blood type AB have the ___ genotype
AB
Blood type O has homozygous ___
OO
How is blood type determined?
Blood type is determined by which antigens are present
A mixture of sample of RBCs with a solution containing either anti-A or anti-B antibodies is observed for RBC agglutination (clumping)
What happens to each blood type?
- Red blood cells of blood type A will clump when anti-A antibody is added, as they have the surface antigen A, but will not clump when anti-B antibody is added, as there are no surface antigens B present with blood type A.
- Anti-B antibodies will clump cells of blood type B, as the surface antigen B is present but there will be no clumping when anti-A antibodies are added
- With blood type AB, clumping will be observed when either anti-A antibodies or anti-B antibodies are added, as both the surface antigen A and B are present on the red blood cells
- With blood type O, no clumping will be observed when either anti-A or anti-B antibodies are added, as there are no surface antigens
Agglutination
a process in which the surface antigens on the red blood cells are bound to antibodies to form a clump followed by hemolysis, or the rupture or destruction of the red blood cells
What should happen first before blood is transfused?
Blood donors and recipients must be matched before blood is transfused
Mismatch combinations of antibodies and antigens would result in:
agglutination of red blood cells and hemolysis
A test in which a donor’s red blood cell antigens are matched with the recipient’s plasma antibodies; usually done when a donor’s red blood cells separated from the plasma fraction
Major cross match
A test done when blood is transfused where the red blood cells are not separated from the plasma, which contains antibodies; the donor’s plasma antibodies must also be matched with the recipients red blood cell antigens to prevent agglutination
Minor cross match
The best donor is the one whose
red blood cell antigens match with the recipients blood type
This blood type is known as universal donors
Blood type O
- a donor of blood type O can donate blood to recipients with blood type A, B and AB in emergency situations
- donors of blood type O do not possess any red blood cell antigens that can cause clumping by reacting with a recipient’s plasma antibodies
A donor of blood type AB can receive blood from ______________ in emergency situations
all other ABO blood types
- Recipients of blood type AB do not possess any plasma antibodies that can cause clumping of the donor’s red blood cell antigens
What happens when there is a mismatched blood transfusion of the ABO blood types?
A transfusion reaction characterized by agglutination, or clumping of the red blood cells, and hemolysis (rupture of red blood cells) occurs
Two types of rhesus blood types
Rh positive and Rh negative
This classification is based on the presence or absence of a protein on the surface of red blood cells known as the D antigen
Rhesus blood type
__________ is the predominant rhesus blood type
Rhesus D positive (Rh+)
D antigens found on red blood cell membrane are ________ molecules which form an integral part of the red blood cell membrane
protein
D antigens are coded for by the dominant ____ genes
D
What is the rhesus blood type if there is presence of the D antigen on red blood cell membrane
Rh+
What is the rhesus blood type if the D antigen on red blood cell membrane is absent?
Rh-
Rh+ can either be homozygous dominant genotype (____) or heterozygous genotype (____)
DD
Dd
Rh- contains two _____ alleles
recessive (dd)
In the RH system, RH+ individuals have D antigens on the ___________________ and no anti-D antibodies in _________
surface of the red blood cells
plasma
Rh- individual lacks D antigens and does not have any anti-D antibodies in plasma. What is an exception?
When an Rh- person develops anti-D antibodies when they are accidentally exposed to D antigens during a blood transfusion or during pregnancy, in the case of an Rh- woman. Anti-D antibodies are formed in the same manner by which our immune system reacts to exposure to a foreign bacterial antigen in developing antibodies.
Anti-D antibodies are of the ______ class, or _______________
IgG, immunoglobin G
What happens to each rhesus blood type during a mismatched transfusion in the Rh system?
- Rh- person with no anti-D antibodies is exposed accidentally to Rh+ blood during transfusion
- Rh- person develops anti-D antibodies
- Then the same Rh- person is exposed by mistake to another transfusion of Rh+ blood
- Anti-D antibodies will bind to Rh+ RBC and cause clumping and hemolysis
Rhesus mismatch poses a problem during pregnancy if a woman is ______
Rh-
- During the first pregnancy the mother’s body is not exposed to baby’s Rh antigen as the baby grows; baby is healthy
- During delivery rupture of placental blood vessels causes some of the fetal Rh+ red blood cells to accidentally enter the maternal blood; this exposes the baby’s Rh+ blood to the mother’s immune system
- The mother is sensitized to the Rh antigen and produces anti-D or anti-RH antibodies
If an Rh- woman conceives a child with an Rh+ man, she will carry an ____ baby in her pregnancy
Rh+
What happens if the same woman (Rh-) is pregnant with a second Rh+ child?
- Circulating anti-D antibodies in the mother’s blood will pass through the placenta into the baby’s body and bind to the baby’s red blood cells to cause rupture and hemolysis
- The baby is born with hemolytic disease of the newborn (HDN); HDN babies are born with high levels of ruptured red blood cells with enlarged spleens and jaundice due to breakdown of hemoglobin
How is the hemolytic disease of the newborn (HDN) prevented?
This condition is prevented by treating the mother immediately after her first delivery with anti-Rh antibodies which will bind to all the red blood cells form the Rh+ newly delivered baby that have escaped into the mother’s body and are circulating in the mother’s blood; the baby’s red blood cells carrying D antigens are bound and blocked by anti-D antibodies and are not exposed to the mother’s immune system to sensitize her.
