Summary BBS2001 Threats and
Defense
Case 1 + lecture thrombosis and hemostasis
Different types of blood cells
Erythrocytes: oxygen transport
Platelets: blood coagulation
Dendritic cells: respond to microbes by producing cytokines that recruit leukocytes and
initiate adaptive immune responses, important bridge between innate and adaptive
Neutrophils: most abundant and defend against bacterial or fungal infection. Usually the first
responders and form pus. Die after having phagocytosed pathogens. Life span: 5-135 hrs.
Eosinophils: allergies, parasitic infections, collagen disease, and disease of the spleen or CNS.
Primarily parasitic infections and inflammatory cells in allergic reactions. Secrete chemicals.
Basophils: release histamine and heparin vasodilation and anticoagulation and attraction
of WBCs to an area respectively. Also secrete chemical signals that attract eosinophils and
neutrophils to an infection site
Lymphocytes:
o B cells: make antibodies that can bind to pathogens, block pathogen invasion,
activate the complement system, and enhance pathogen destruction humoral
immunity
o T cells:
CD4+ helper cells: maturation of B cells into plasma cells and memory B cells
and help activate cytotoxic T cells and macrophages, activated by MHC Class
II molecules and secrete cytokines
CD8+ cytotoxic cells: cause lysis of virus-infected and tumour cells
Memory T cells: long lived and can quickly expand to large numbers of
effector T cells upon re-exposure to the antigen
o NK cells: able to kill cells of the body that do not display MHC Class I molecules or
display stress markers.
Monocytes: phagocytotic function, long lived also present pieces of pathogens to T cells
so that the pathogens may be recognized again and killed. Will leave the bloodstream and
turn into macrophages, which remove dead cells and attack microorganisms
,The inflammatory process
Function: eliminate intial cause of cell injury, clear out necrotic cells and tissues damaged
from the original insult, initiate tissue repair
Five signs:
o Heat (calor): increased blood flow and metabolic activity
o Pain (dolor): release of chemicals such as bradykinin and histamine
o Redness (rubor): increased blood flow
o Swelling (tumor): increased permeability of the blood vessels leakage of plasma
proteins and fluid into the tissue
o Loss of function (function laesa): increased neurological reflex
Steps:
1. Tissue is damaged allowing access of pathogens and releasing PAMPs and DAMPs
2. Mast cells detect the PAMPs and DAMPs and release the mediators of inflammation
(Mol)
3. Mols raise the alarm and cause blood vessels to open in the area, allowing access to
phagocytes
4. Phagocytes then attempt to neutralize the pathogens and clean up the damage
5. Platelets also enter the area and begin the repair process
6. The influx of blood and fluid causes the swelling, pain and heat, associated with
inflammation
In a normal state, endothelial cells secrete platelet inhibitors like nitric oxide and
prostacyclin, so no coagulation occurs
Platelets
Platelets need strong attachments to get attached to the vessel wall, due to high forces
rolling effect
Receptors cluster together and form a strong place for attachments
Different types of platelets: aggregating, procoagulant, coated, secretory
,Hemostasis and coagulation
Consists of three major steps
1. Vasoconstriction
2. Temorary blockage of the damage by a platelet plug
3. Coagulation
Primary hemostasis Secondary hemostasis
The interaction between the blood vessel, von The cascade of enzymatic reactions that
Willebrand factor, and platelets in order to ultimately results in the conversion of
form the initial platelet plug fibrinogen to fibrin monomers
Components: Endothelial cells, platelets, Components: Cells, enzymatic and non-
adhesive proteins including vWf and collagen, enzymatic coagulation factors,
and facilitators including thrombin phosphatidylserine, and calcium
Sequence of Events: platelet adhesion, platelet Sequence of Events: Initiation of thrombin
activation, and the platelet plug formation generation, amplification of thrombin
generation, propagation of thrombin
generation, and fibrin formation
Final result: formation of a platelet plug Final result: formation of a stable, fibrin clot
Serves as an immediate response to the Produces a reinforcement in the platelet plug
vascular injury, limiting bleeding from fibrin, stabilizing it
When a vessel is ruptured, procoagulants from the area of tissue damage become activated
and override the anticoagulants, and then a blood clot develops
Three essential steps:
1. In response to the injury, a cascade of chemical reactions occurs. It involves a dozen
blood coagulation factors and the result is formation of a complex of activated
substances called prothrombin activator
2. The prothrombin activator catalyses conversion of prothrombin into thrombin
3. Thrombin acts as an enzyme to convert fibrinogen into fibrin fibres that encourage
platelets, blood cells and plasma to form the cloth
Prothrombin and thrombin
Prothrombin is an alpha2-globulin and is formed by the liver vitamin K required
Prothrombin will split into thrombin
Fibrinogen to fibrin – formation of the clot
Fibrinogen
Large molecule, so normally does not leak into interstitial fluids; formed by the liver
Action of thrombin on fibrinogen to form fibrin
Thrombin acts on fibrinogen to remove four peptides to form one molecule of fibrin
monomer, which can polymerise with other fibrin monomers to form fibrin fibres
First: weak, non-covalent hydrogen bonds (not cross-linked)
Fibrin-stabilizing factor: released by platelets, activated by thrombin and then acts as an
enzyme to cause covalent bonds and multiple cross-linkages
Blood clot
Composed of fibrin fibres, blood cells, platelets and plasma
Also adheres to damaged surfaces of the blood vessel to prevent further blood loss
Formation of the prothrombin activator
Three things can cause the conversion of prothrombin to thrombin and subsequent clotting
steps
1. Trauma to the vascular wall and adjacent tissues
2. Trauma to the blood
, 3. Contact of the blood with damaged endothelial cells or with collagen and other tissue
elements outside the blood vessel
Can be activated via the extrinsic (trauma to vascular wall) or intrinsic pathway (blood)
The extrinsic pathway
1. Release of tissue factor: tissue factor (TF) or tissue thromboplastin is released composed
of phospholipids and a lipoprotein complex that functions as proteolytic enzyme
2. Activation of factor X: lipoprotein complex complexes with blood coagulation Factor VII and
acts enzymatically on Factor X to from Xa in the presence of calcium
3. Effect of Xa: Xa combines with tissue phospholipids (part of TF or released from platelets)
and Factor V prothrombin activator: splits prothrombin into thrombin when calcium is
present
- Xa is the actual protease that causes splitting of prothrombin to thrombin
- Va accelerates this protease activity
- Platelet phospholipids act as a vehicle that further accelerates the process
The intrinsic pathway
1. Blood trauma causes (1) activation of Factor XII and (2) release of platelet phospholipids:
contact of Factor XII with collagen or a wettable surface causes a molecular configuration
that converts XII into a proteolytic enzyme XIIa. Damaged platelets release phospholipids
that contain lipoprotein platelet factor 3, a negatively charged phospholipid
2. Activation of Factor XI: XIIa acts on XI to activate it
3. Activation of Factor IX by Xia
4. Activation of Factor X: IXa actw with VIIIa and platelet phospholipids and platelet factor 3 to
activate Factor X
- Classic haemophilia: no Factor VIII; Haemophilia B: no Factor IX; Haemophilia C: no
Factor XI
- Thrombocytopenia: no platelets
5. Formation of prothrombin activator: Xa combines with Factor V and platelet or tissue
phospholipids to form the prothrombin activator and convert prothrombin into thrombin
Leukocyte migration during inflammation
1. Capture: activated macrophages by pathogens release cytokines (IL-1, TNF- and
chemokines) endothelial cells near site of infection express cellular adhesion molecules
(selectins)
2. Rolling: leukocytes bind to selectin molecules and cause leukocytes to slow down and begin
rolling along the inner surface of the vessel wall. During this rolling, bonds are formed and
broken between selectins and ligands
3. Arrest: chemokines released by macrophages activate rolling leukocytes and cause integrin
molecules to switch form low to high-affinity state. Integrin binds tightly to complementary
receptors on endothelial cells, which causes immobilization of the leukocytes
4. Crawling
5. Diapedesion/transmigration: leukocytes are spread out over the endothelial cells and
leukocytes pass through gaps between the cells = diapedesis. Transmigration occurs as
PECAM proteins interact and pull the cell through. Once through it must penetrate the
basement membrane.
Defense
Case 1 + lecture thrombosis and hemostasis
Different types of blood cells
Erythrocytes: oxygen transport
Platelets: blood coagulation
Dendritic cells: respond to microbes by producing cytokines that recruit leukocytes and
initiate adaptive immune responses, important bridge between innate and adaptive
Neutrophils: most abundant and defend against bacterial or fungal infection. Usually the first
responders and form pus. Die after having phagocytosed pathogens. Life span: 5-135 hrs.
Eosinophils: allergies, parasitic infections, collagen disease, and disease of the spleen or CNS.
Primarily parasitic infections and inflammatory cells in allergic reactions. Secrete chemicals.
Basophils: release histamine and heparin vasodilation and anticoagulation and attraction
of WBCs to an area respectively. Also secrete chemical signals that attract eosinophils and
neutrophils to an infection site
Lymphocytes:
o B cells: make antibodies that can bind to pathogens, block pathogen invasion,
activate the complement system, and enhance pathogen destruction humoral
immunity
o T cells:
CD4+ helper cells: maturation of B cells into plasma cells and memory B cells
and help activate cytotoxic T cells and macrophages, activated by MHC Class
II molecules and secrete cytokines
CD8+ cytotoxic cells: cause lysis of virus-infected and tumour cells
Memory T cells: long lived and can quickly expand to large numbers of
effector T cells upon re-exposure to the antigen
o NK cells: able to kill cells of the body that do not display MHC Class I molecules or
display stress markers.
Monocytes: phagocytotic function, long lived also present pieces of pathogens to T cells
so that the pathogens may be recognized again and killed. Will leave the bloodstream and
turn into macrophages, which remove dead cells and attack microorganisms
,The inflammatory process
Function: eliminate intial cause of cell injury, clear out necrotic cells and tissues damaged
from the original insult, initiate tissue repair
Five signs:
o Heat (calor): increased blood flow and metabolic activity
o Pain (dolor): release of chemicals such as bradykinin and histamine
o Redness (rubor): increased blood flow
o Swelling (tumor): increased permeability of the blood vessels leakage of plasma
proteins and fluid into the tissue
o Loss of function (function laesa): increased neurological reflex
Steps:
1. Tissue is damaged allowing access of pathogens and releasing PAMPs and DAMPs
2. Mast cells detect the PAMPs and DAMPs and release the mediators of inflammation
(Mol)
3. Mols raise the alarm and cause blood vessels to open in the area, allowing access to
phagocytes
4. Phagocytes then attempt to neutralize the pathogens and clean up the damage
5. Platelets also enter the area and begin the repair process
6. The influx of blood and fluid causes the swelling, pain and heat, associated with
inflammation
In a normal state, endothelial cells secrete platelet inhibitors like nitric oxide and
prostacyclin, so no coagulation occurs
Platelets
Platelets need strong attachments to get attached to the vessel wall, due to high forces
rolling effect
Receptors cluster together and form a strong place for attachments
Different types of platelets: aggregating, procoagulant, coated, secretory
,Hemostasis and coagulation
Consists of three major steps
1. Vasoconstriction
2. Temorary blockage of the damage by a platelet plug
3. Coagulation
Primary hemostasis Secondary hemostasis
The interaction between the blood vessel, von The cascade of enzymatic reactions that
Willebrand factor, and platelets in order to ultimately results in the conversion of
form the initial platelet plug fibrinogen to fibrin monomers
Components: Endothelial cells, platelets, Components: Cells, enzymatic and non-
adhesive proteins including vWf and collagen, enzymatic coagulation factors,
and facilitators including thrombin phosphatidylserine, and calcium
Sequence of Events: platelet adhesion, platelet Sequence of Events: Initiation of thrombin
activation, and the platelet plug formation generation, amplification of thrombin
generation, propagation of thrombin
generation, and fibrin formation
Final result: formation of a platelet plug Final result: formation of a stable, fibrin clot
Serves as an immediate response to the Produces a reinforcement in the platelet plug
vascular injury, limiting bleeding from fibrin, stabilizing it
When a vessel is ruptured, procoagulants from the area of tissue damage become activated
and override the anticoagulants, and then a blood clot develops
Three essential steps:
1. In response to the injury, a cascade of chemical reactions occurs. It involves a dozen
blood coagulation factors and the result is formation of a complex of activated
substances called prothrombin activator
2. The prothrombin activator catalyses conversion of prothrombin into thrombin
3. Thrombin acts as an enzyme to convert fibrinogen into fibrin fibres that encourage
platelets, blood cells and plasma to form the cloth
Prothrombin and thrombin
Prothrombin is an alpha2-globulin and is formed by the liver vitamin K required
Prothrombin will split into thrombin
Fibrinogen to fibrin – formation of the clot
Fibrinogen
Large molecule, so normally does not leak into interstitial fluids; formed by the liver
Action of thrombin on fibrinogen to form fibrin
Thrombin acts on fibrinogen to remove four peptides to form one molecule of fibrin
monomer, which can polymerise with other fibrin monomers to form fibrin fibres
First: weak, non-covalent hydrogen bonds (not cross-linked)
Fibrin-stabilizing factor: released by platelets, activated by thrombin and then acts as an
enzyme to cause covalent bonds and multiple cross-linkages
Blood clot
Composed of fibrin fibres, blood cells, platelets and plasma
Also adheres to damaged surfaces of the blood vessel to prevent further blood loss
Formation of the prothrombin activator
Three things can cause the conversion of prothrombin to thrombin and subsequent clotting
steps
1. Trauma to the vascular wall and adjacent tissues
2. Trauma to the blood
, 3. Contact of the blood with damaged endothelial cells or with collagen and other tissue
elements outside the blood vessel
Can be activated via the extrinsic (trauma to vascular wall) or intrinsic pathway (blood)
The extrinsic pathway
1. Release of tissue factor: tissue factor (TF) or tissue thromboplastin is released composed
of phospholipids and a lipoprotein complex that functions as proteolytic enzyme
2. Activation of factor X: lipoprotein complex complexes with blood coagulation Factor VII and
acts enzymatically on Factor X to from Xa in the presence of calcium
3. Effect of Xa: Xa combines with tissue phospholipids (part of TF or released from platelets)
and Factor V prothrombin activator: splits prothrombin into thrombin when calcium is
present
- Xa is the actual protease that causes splitting of prothrombin to thrombin
- Va accelerates this protease activity
- Platelet phospholipids act as a vehicle that further accelerates the process
The intrinsic pathway
1. Blood trauma causes (1) activation of Factor XII and (2) release of platelet phospholipids:
contact of Factor XII with collagen or a wettable surface causes a molecular configuration
that converts XII into a proteolytic enzyme XIIa. Damaged platelets release phospholipids
that contain lipoprotein platelet factor 3, a negatively charged phospholipid
2. Activation of Factor XI: XIIa acts on XI to activate it
3. Activation of Factor IX by Xia
4. Activation of Factor X: IXa actw with VIIIa and platelet phospholipids and platelet factor 3 to
activate Factor X
- Classic haemophilia: no Factor VIII; Haemophilia B: no Factor IX; Haemophilia C: no
Factor XI
- Thrombocytopenia: no platelets
5. Formation of prothrombin activator: Xa combines with Factor V and platelet or tissue
phospholipids to form the prothrombin activator and convert prothrombin into thrombin
Leukocyte migration during inflammation
1. Capture: activated macrophages by pathogens release cytokines (IL-1, TNF- and
chemokines) endothelial cells near site of infection express cellular adhesion molecules
(selectins)
2. Rolling: leukocytes bind to selectin molecules and cause leukocytes to slow down and begin
rolling along the inner surface of the vessel wall. During this rolling, bonds are formed and
broken between selectins and ligands
3. Arrest: chemokines released by macrophages activate rolling leukocytes and cause integrin
molecules to switch form low to high-affinity state. Integrin binds tightly to complementary
receptors on endothelial cells, which causes immobilization of the leukocytes
4. Crawling
5. Diapedesion/transmigration: leukocytes are spread out over the endothelial cells and
leukocytes pass through gaps between the cells = diapedesis. Transmigration occurs as
PECAM proteins interact and pull the cell through. Once through it must penetrate the
basement membrane.
