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Summary BBS2001 - Threats and defence mechanisms
Summary BBS2001 - Threats and defence mechanisms
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Voorbeeld 4 van de 44 pagina's
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Voorbeeld van de inhoud
Innate immune systemHemostasis
Hemostasis regulates blood clothing, platelet activation and vascular repair. Vessel damage recruits
platelets to adhere to the damaged site and aggregate through interactions of platelet receptors with
extracellular ligands and soluble proteins. The vascular damage-induced exposure of subendothelial
Tissue Factor generates amounts of thrombin.
There are three stages in the formation of a blood clot:
- Adhesion
- Activation
- Aggregation
Primary hemostasis – platelet adhesion and aggregation
Thrombopoiesis → formation of platelets.
Platelets bud off megakaryocytes via protrusions,
which are large cells developed by undergoing
mitosis several times without undergoing nuclear or
cytoplasmic division, which results in a polyploid
cell with a lobed nucleus. Megakaryocytes have an
invaginated membrane system (IMS).
Platelets:
- Oval structure with wrinkles
- No nucleus
- Change shape → can spread
- Contains canals
- Contain granules with bioactive compounds
Active platelets are carried by granules.
Platelets are present 150 to 400 million per ml and
circulate in the blood for about 10 days. Types:
- Aggregation platelet → promote platelet-platelet adhesion
- Procoagulant platelets → expose negatively charged phospholipid PF3, necessary for intrinsic
pathway of coagulation.
- Secretory platelets → secrete procoagulant factors to promote clotting
- Coated platelets → strong coagulation activators
Platelets signal mainly over
GPCRs
Platelet activation → transduction → amplification (calcium
rise) → feedback
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,Platelet adhesion → platelets to the side
of damage.
Adhesion is initiated by binding of von-
Willebrand-factor (VWF), for instand to
collagen in the subendothelial matrix, to
the receptor GPIb-IX-V. Binding of
platelets leads to the release of contents
of intracellular granules, including
serotonin, ADP, and platelet-activating-
factor (PAF).
- VWF → protein secreted from endothelial cells and megakaryocytes that is always present in
soluble state in plasma as well as in the immobilized state in subendothelial matrix. Soluble
VWF only binds with low affinity to GPIb-IX-V, therefore only in case of injury immobilized
VWF will be exposed to the lumen and can fully bind to its receptor.
- Collagen → binds to GPVI and is located in the subendothelial matrix and gets released upon
injury, binding to GPVI on an inactive platelet and activating it.
- PAF → sets up a positive feedback loop by activating more platelets and initiates pathways
that lead to thromboxane A2 production.
- Thromboxane → promotes aggregation and release of granules from platelets, acts on TPα
and TPβ.
- Fibronectin → promotes spreading of platelets at site of injury, the adhesion and migration
of neutrophils, monocytes, fibroblasts, and endothelial cells into the wound region, and the
migration of epidermal cells through the granulation tissue.
- Fibrinogen → the formation of fibrin that binds together platelets and some plasma proteins
in a hemostatic plug.
- Integrin αIIbβ3 → plays a central role in platelet functions, hemostasis, and arterial
thrombosis.
Greatest force is on the blood vessel wall, so cells are pushed towards the vessel wall
Antiplatelet drugs (bloedverdunners):
- Clopidogrel, prasugrel, ticagrelor → target ADP receptor P2Y12
- Aspirin → targets the enzyme cyclooxygenase (COX), that generates thromboxane A2.
- Vorapaxar → Blocks protease-activated receptor (PAR)-1, receptor for thrombin.
- Reopro, integrilin, tirofiban → intravenous drug that blocks integrin αIIbβ3.
Platelet aggregation → clumping together of platelets in blood.
2
,Platelet defects:
- Von Willebrand factor disease → deficiency in VWF
- Bernard-Soulier syndrome → deficiency/defect in GPIb-α
- Glanzmann Thrombasthenia → deficiency/defect in αIIbβ3
- Macrothrombocytopenia(s) → deficiencies in cytoskeleton.
Secondary hemostasis – blood coagulation and fibrinolysis
Deposition of insoluble fibrin, generated by proteolytic coagulation cascade. Occurs simultaneously
to platelet aggregation and creates a fibrin plug that stabilizes the platelet plug to form a clot. In the
blood are a lot of inactive coagulation factors.
The enzymes activating factors is are serine proteases.
Extrinsic pathway
Tissue factor (TF) triggers the coagulation reaction.
- TF binds to VIIa, forming the TF-factor-VIIa-complex, which activates FX, forming FXa
- FXa combines with FVa, phospholipids, and calcium, forming the prothrombinase complex
- Prothrombinase complex activates prothrombin into thrombin
- Thrombin converts fibrinogen into firbin, activates platelets, and makes a feedback loop.
Thrombin can directly activate FXI, FVIII, and FV.
Intrinsic pathway
The intrinsic pathway is activated by a foreign surface (negatively charged) or bacteria.
- Factor XII is activated and will activate FXI into FXIa.
- FXIa activates FIX into FIXa, which will combine with FVIIIa and phospholipids forming the
tenase complex, which can activate FX into FXa, and form the prothrombinase.
Common pathway
- Thrombin cleaves fibrinogen to generate insoluble fibrin, activates platelets via cleavage of
PAR1 and PAR4 and generates a positive feedback loop via activation of the intrinsic and a
negative feedback loop via activated protein C, which inactivates VIIIa and Va.
3
, Adenosine diphosphate (ADP) → causes more platelets to stick to the area and release their
contents.
Serotonin and thromboxane A2→ messengers that enhance vascular spasm and platelet aggregation.
Regulation of blood coagulation
- Antithrombin → blocks thrombin and FIXa and FXa.
o Activity is enhanced by heparin
- α2-macroglobulin → inhibits thrombin
- activated protein C → cleaves FVIII and FV
Fibrinolysis
Fibrinolysis is the clean-up for the clots that are not needed anymore. This is an important
process because without the removal of unneeded clots the blood vessels would eventually be
completely blocked. This process is done by a fibrin-digesting enzyme called plasmin. Plasmin is
produced when the plasma protein plasminogen is activated. Plasminogen is already built into the
clot in its inactive form. It remains there until an appropriate signal reaches it.
Plasminogen can be activated by either epithelial cells that secrete tissue plasminogen activator
(tPA)or factor XII, protein C and thrombin. It begins within two days and continues slowly over
several days until the clot is finally dissolved. Plasmin is reduced to the area of the clot. When it
dissolves in the plasma it is quickly destroyed by circulating enzymes.
Genetic disorders:
- Hemophilia A → Deficiency in factor VIII
- Hemophilia B → Deficiency in factor IX
- Hemophilia C → Deficiency in factor XI
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