Platelets, clotting, and thrombosis Flashcards
What is haemostasis?
The stopping of bleeding
What is thrombosis
Unwanted blood clotting
What are the 4 stages of haemostasis
Vasoconstriction
Platelet activation
Coagulation cascade and plug formation
Fibrinolysis
Which factors promote vasoconstriction
Serotonin and thromboxin a2
Which coagulation component further promotes vasoconstriction
Fibrinopeptides
What is the development pathway of a platelet
Myeloid stem cell
Megakaryocyte
Proplatelet
Platelet
How many platelets does each megakaryocyte give rise to
~1000
What are megakaryocytes
Precursor to platelets
Undergone multiple replications where they do not replicate
Can reach 128n
Where do megakaryocytes reside
Bone marrow
Where do platelets reside
Blood
How does megakaryocyte release platelets into blood
Megakaryocyte sticks to sinusoidal endothelial cell
Proplatelet structures elongate off the megakaryocyte and are pushed into the blood vessel
Platelets bud off into flowing blood
What is the role of membrane proteins on platelets
Dictate how they respond to environment
Triggers activation
What is the role of open membrane on platelets
Canicular membrane created by invaginations of the plasma membrane provides large sa for coagulation proteins to be absorbed
What are the storage proteins in paltelets
Alpha granules store big proteins e.g. fibrinogen, factor V, vWF
Dense granules store smaller molecules e.g. calcium ions and serotonin
Storage granules are discharged on activation
What makes up the platelet phospholipid
Plasma membrane and open canalicular system
How do non-active platelets reside in blood vessels
Platelets are pushed to the side of blood vessel
Endothelial cells release platelet inhibitors PG12, NO, and CD39
How do platelets become activated
Damage exposes subendothelial proteins
Platelets cell surface receptors recognise these proteins
Recognition triggers platelet activation
What proteins trigger platelet activation
Subendothelial proteins collagen and laminins
How does platelets morphology change as they become activated
Filopodia protrusions allow them to stick to site of damage
Sheets of lamellipodia membrane fill in the gaps
Which proteins mediate platelet tethering
GP1b on platelet tethers to vWF on collagen
Fast on-off binding rate allows rolling
Which protein is responsible for platelet activation
GPVI on platelet binding to collagen
What happens when the platelet is activated
Degranulation of alpha granules
Release of ADP, thromboxane, and A2 act as positive feedback mediators
Coagulation cascade
Integrins become activated
What mediates adhesion of platelets and thrombus growth
Integrin
What is the role of chemokines
Attract wbc - required for phagocytosis
What is the role of cytokines
Activate wbc - increase immune response
What is the role of growth factors
Stimulate surrounding cells e.g. endothelial to grow and repair
How does lipid flipping aid in repair
On inactive platelets, phosphatidylserine is on inside of lipid bilayer
Activated platelets have phosphatidylserine flip, making the surface of the platelet negatively charged
Coagulation factors are positively charged so they are attracted to platelet plug
6 steps of coagulation
Vessel injury
Activation of coagulation factors on TF, collagen, and platelet
Amplification cascade
Thrombin generation
Fibrinogen –> fibrin
Clot stabilisation
What is the role of thrombin
Activate platelets and fibrin
What is the role of TF
Transmembrane protein that is on surface of smooth muscle
Exposed to blood when there is damage
leads to thrombin production by extrinsic pathway
What is responsible for clot retraction
Platelet integrin alphaIIbeta3
This links fibrin to platelet actin cytoskeleton
What process does plug autodigest by
Fibrinolysis
What are physical limitations of coagulation
Coagulation factor inhibitors
Protein C and S - inhibit clot formation process
Blood flow - too rapid and clot will be washed away
Fibrinolysis - correct fibrinolysis prevents excessive bleeding or prolonged clot presence
What is the role of TFPI
Inhibits TF, FVIIa, FXa
Negative regulation to prevent excessive clotting
What is the role of protein C and S in coagulation cascade
Protein C is a serine protease released by endothelial cells and platelets
Protein C is activated by thrombin and enhanced by protein S
It negatively regulates FVIII and FV
What is the role of antithrombin in coagulation cascade
Inhibits thrombin to prevent excess clot formation
What is the key enzyme for clot degradation
Plasmin from inactive plasminogen
Tissue plasminogen activator released by injured endothelial cells activates plasminogen
What is arterial thrombosis
Formation of a blood clot within an artery
Often caused by platelet aggregation at site of atherosclerotic plaque rupture
Build up of fatty deposits and immune cells -chronic inflammatory rection underneath endothelial cells
What is atherosclerosis
Build up of plaque in arteries that forms over time
Fat is in form of LDL
4 stages of atherosclerosis progression
Fatty streak
Intermediate lesion
Lesion vulnerable to rupture
Advanced obstruction lesion
Risk factors for arterial thrombosis
Environmental: high cholesterol, physical inactivity, smoking, high blood pressure, obesity
Inherited: familial tendency, gene susceptibility
What is venous thrombosis
Formation of blood clots
DVT - usually in legs
Superficial - closer to skins surface
Endothelium remains intact
Inherited risk factors for venous thrombosis
FV Leiden
Deficiency in protein C, S, or antithrombin
Prothrombin polymorphism (high levels)
Acquired risk factors for venous thrombosis
Prolonged immobility - slow blood flow and pooling
Postoperative
Cancer - hyper-coagulable state or tumor pushes on vessels
Contraceptive pill - oestrogen is associated with high levels of coagulation factors
Heart failure
Varicose veins
Treatments of venous thrombosis
Warfarin - Vitamin k antagonist so prevents FXa, FVIIa, FIXa, and thrombin
Heparin - activates antithrombin to inhibit thrombin and FX
Limitations of warfarin and heparin
Genetic polymorphisms and drug-drug/food interactions cause varying anti-coagulation ability
Dose varies between patients
Coagulation monitoring required
What oral anticoagulants can be used for venous thrombosis
Apixaban
Edoxaban
Rivaroxaban
Dabigatran
Benefits of other oral anticoagulants than warfarin and heparin
Less intercranial bleeding
Predictable anticoagulant effect, less monitoring
Quick onset and offset
Fewer drug-food interactions
Used for deep vein thrombosis, pulmonary embolism, post-operative for hip and knee replacements, stroke prevention in atrial fibrillation
What is atrial fibrillation
Abnormal heart rhythm caused by atria not beating properly
Causing abnormal blood flow, increasing risk of ischaemic stroke and dementia
How can ischaemic stroke be treated
Clot busters
Streptokinase binds to plasminogen
Activated plasminogen will activate plasmin
Plasmin degrades fibrin meshwork
Streptokinase is only effective within 3 hours of event
