Pathophysiology of clotting Flashcards
What components are within the ECF (plasma)?
- erythrocytes
- leukocytes
- platelets
What is plasma?
pale white watery solution of electrolytes, plasma proteins, carbohydrates & lipids
What does pink blood indicate?
haemoglobin has been released by haemolysis (rupture of erythrocytes)
What does brown/green blood indicate?
high bilirubin (erythrocyte breakdown), liver or gallbladder issue
What does cloudy blood indicate?
high levels of cryoglobulins (immunoglobulin) - abnormal increase in viscosity (with cooling), which leads to vessel obstruction + local thrombosis
What is the hematocrit made of?
red blood cells (erythrocytes)
How do you establish the hematocrit %?
height of erythrocytes/total height
What are the 3 principal proteins found in plasma?
- albumin
- fibrinogen
- immunoglobulins
What is the role of albumin?
oncotic pressure, binds steroids, Y3 bilirubin, bile salts, FA)
What is the role of fibrinogen?
clotting protein, precursor fibrin
What is the role of immunoglobulins?
humoral immunity from plasma/B cells
what is factor 1 in the blood coagulation cascade?
fibrinogen
what is factor 2 in the blood coagulation cascade?
prothrombin
what is factor 3 in the blood coagulation cascade?
tissue factor
How many plasma proteins are involved in the blood coagulation cascades?
14 (factor 1-13 & vWF)
What is vWF?
Von Willebrand factor
What is the most prevalent factor in plasma?
albumin
What is fibrinogen important for?
important in blood clotting
What is the role of vWF (Von Wilebrand Factor)?
Mediates platelet adhesion to damaged vascular subendothelium & subsequently platelet aggregation
What cells in blood play a big role in determining blood viscosity?
erythrocytes
Why do erythrocytes have a non-nucleated biconcave disc shape?
maximising SA:Vol
What is the main component in erythrocytes?
haemoglobin
What maintains the shape of erythrocytes?
cytoskeleton
What are erythrocytes anchored to?
plasma membrane
What are the 3 main functions of erythrocytes?
- O2 carriage from lungs to systemic system.
- CO2 carriage from tissues to lungs.
3.Buffering of acids/bases
What are 2 types of white blood cells (leukocytes) are there?
granulocytes & non-granular
What are the 3 types of granulocytes?
- neutrophils
- eosinophils
- basophils
What is the role of neutrophils?
phagocytose bacteria
What is the role of eosinophils?
combat parasites & viruses
What is the role of basophils?
release IL-4, histamine, heparin & peroxidase
What are the 2 types of non-granular leukocytes?
- lymphocytes
- monocytes
What is the function of lymphocytes?
mature into T cells & B cells (plasma cells)
What is the function of monocytes?
macrophages & dendritic cells
Where are platelets made?
bud off from megakaryocytes in bone marrow (TPO - thrombopoietin & IL-3 dependent)
Describe the feedback mechanism by which platelets are made?
- Platelet receptor TPO
- Abundant platelets bind TPO
- Megakaryocytes not generated
- Platelets not made
- Receptors don’t bind TPO
- TPO stimulates megakaryocytes production
- Platelets generated
What nucleus-free fragments are found in a platelet?
- mitochondria
- lysosomes
- peroxisomes
- alpha granules (VWF, fibrinogen, clotting factor)
- dense-core granules (ATP, ADP, Ca2+)
Why is it beneficial for platelets to have a circumferential band tubulin microtubules in its inner skeleton?
allows for the ability for the platelets to change shape?
What is haemostasis?
the prevention of haemorrhage
What is used in haemostasis?
- vasoconstriction (e.g. thromboxane A, serotonin, thrombin & endothelin-1)
- increased tissue pressure (decreased transmural pressure - pressure difference between inside & outside of blood vessel)
- platelet plug (transient) - small breaches in vascular endothelium
- stabilisation of weak platelet plug with fibrin
What are the 3 roles of the platelet plug?
- adhesion
- activation
- aggression
How is the platelet plug with fibrin?
with the addition of fibrin - coagulation/clot formation, a semisolid mass of platelet + fibrin mesh with trapped cells + serum
What occurs during platelet adhesion?
- platelet adhesion mediated by platelets receptors bound to ligands
- breach of endothelium exposes:
- plasma VWF, which binds to collagen exposed in damaged tissue & platelet receptors
- endothelial cell VWF factor release also triggered - forming addition links
What leads to platelet activation?
ligand binding leads to conformation change in receptors. This leads to an intracellular signalling cascade being initiated
What is released following platelet activation?
- dense storage granules (ATP, ADP, serotonin, Ca2+)
- alpha granules (vWF, clotting factor V, fibrinogen)
What cytoskeletal changes occur following platelet activation?
- lamellipodium/filopodia
What occurs during platelet aggression?
- activation leads to conformation change in the receptors
- this allows it to bind to fibrinogen - forming molecular bridges between platelets
What is a blood clot composed of?
semisolid mass of:
- erythrocytes
- leukocytes
- serum
- mesh of fibrin (and platelets)
What is the main process that occurs during platelet aggression?
activation triggers chain reaction converting precursors to activated factors
- controlled proteolysis amplifies clotting signals
What is a thrombus?
intravascular clot (not wanted)
Describe the intrinsic pathway of clotting
initiated by factors within blood in contact with the negatively charged membrane surface of the activated platelet.
- this causes a cascade of protease reactions. Positive feedback acts at several upstream levels, ending in activated FACTOR XA (FACTOR 10)
Describe the extrinsic pathway of clotting
Injury to endothelium allows ‘tissue factor’ (receptor) in subendothelial cells to become activated when blood factor VII in contact
- this leads to activated FACTOR XA (FACTOR 10)
What is the function of FACTOR XA (FACTOR 10)?
FACTOR XA (FACOTR10) from both intrinsic & extrinsic pathways enters a common pathway to generate THROMBIN (enzyme) and produce stable fibrin?
What does generation of thrombin (enzyme) lead to?
production of stable fibrin
Do velocities increase of decrease from wall to centre?
increase (thin layer next to wall cannot move)
What is laminar flow?
parabolic profile, with maximal velocity (Vmax) at centre
What is abnormal (turbulent) flow?
non-laminar blood flow leads to endothelial injury
What can cause turbulent flow?
- local stenosis (narrowing of blood vessel)
- large radium (e.g. aorta)
- high velocity (e.g. high CO - cardiac output)
What is arterial thrombosis?
the formation of an atherothrombosis (clot in artery), following erosion or rupture of atherosclerotic plaque
What is the Virchow triad?
the 3 primary factors which can lead to the development of thrombosis:
- Endothelial injury
- Abnormal blood flow
- Hyper-coagulability
What is stenosis?
The narrow of a blood vessel
What is an example of abnormal blood flow?
turbulent or stasis (plane/car/bedrest)
What is an example of endothelial injury?
platelet activation (inflammation/cholesterol)
Why might a person experience hyper-coagulability?
inherited or through infection or injury
What do homeostatic mechanisms to prevent haemostasis aim to achieve?
Prevention of blood clot development:
- balance between pathological states of inadequacy & overactive clotting
Describe how homeostatic mechanisms promote an anti-thrombotic state
- normal endothelial cells maintain normal blood fluidity through paracrine factors & anticoagulant factors
- paracrine factors - e.g. prostacyclin promotes vasodilation, nitric oxide (NO) inhibits platelet adhesion & aggregation
Describe how homeostatic mechanisms promote a pro-thrombotic state
- event of vascular damage
- hypoxia (expression of procoagulants)
