Haemostasis - Platelets Flashcards
what is haemostaiss?
this is a physiological process which stops the bleeding at the site of vascular injury
what does haemostasis do?
refers to process in which blood coagulation is initiated and terminated in a tightly controlled fashion
what happens when the ‘vessel’ is healed/remodelled?
clot dissolution (removal)
haemostasis happens whilst still maintaining?
blood flow elsewhere in the circulation
Haemostasis is a defence mechanism that does what?
it preserves the integrity of the vascular system
what are the 5 key players in haemostasis?
blood vessels
platelets
coagulation factors
coagulation inhibitors
fibrinolytic factors
what is the first step of haemostasis?
vasoconstriction - restricts blood flow in and to the damaged vessel
what is the second step of haemostasis?
platelets aggregate and form a platelet plug
termed as ‘Primary haemostasis’
what is the third step of haemostasis?
coagulation cascade activated to facilitate thrombin generation
this proteolyzes soluble fibrinogen to yield insoluble fibrin
referred to as ‘Secondary haemostasis’
what is the fourth step of haemostasis?
fibrinolysis - removal of the clot in a controlled fashion
why is haemostasis important?
essential to preserve the high pressure of vascular system
response must be rapid but regulated to prevent blood loss and also stop inappropriate clot formation - localised to maintain flow elsewhere
inappropriate coagulation could block vessels
restriction of blood flow
o2 starvation
cell death - brain, heart, other organs, limbs
haemostasis has an important role in?
in preventing microbes from gaining access to the circulation - link to innate immune system
pathological condition and risks associated with haemostasis?
haemophilia
DVTs
pulmonary embolism
surgical interventions - blood loss and fluid replacement causing a dilution of coagulation factors
liver disease
leukaemias
how is haemostasis so speedy?
platelets are circulating in blood in high numbers
ready to be activated at the site of injury and undergo rapid amplification of activation
coagulation proteins (made in liver) circulate/stored as inactive precursors (zymogens)
ALL COMPONENTS READY TO GO IN CIRCULATION
why is haemostasis localised?
platelets use receptors to sense proteins that are only exposed during vascular injury
collagens in ECM
Von Willebran Factor (VWF) in blood can then bind collagen and bridge the platelet to the ECM
platelets in avian species are different to other platelets, why?
platelets in avian species have a nucleus but platelets are anucleate in other species
lifespan of platelets?
up to 10 days species dependent
platelets?
cell fragments produced by bone marrow
production of platelets regulated by?
by the hormone thrombopoietin that is made by the liver and kidney
what disease may reduce platelet numbers?
liver disease
what is thrombocytopenia?
platelet deficiency
normal ranges of platelet numbers?
*Humans 150-400 x 109/L
*Most animal species 200-500 x 109/L
*Rodents at least 900 x 109/L
what are platelets sometimes called and give an example of when?
thrombocytes
e.g. in avian species
size of platelets?
2-4 micrometres diameter, varies between species
describe resting platelets?
discoid in shape
stain dark w/ visible red to pink granules
do not adhere to healthy vessel wall or aggregate w/ each other
vessel wall also releases factors that keep platelets inactive e.g. prostacyxlin
extremely sensitive to activation - hard to maintain storage
thrombus formation needs to be?
rapid
localised
stable - doesn’t have chunks embolising
coordinated - rapid activation of platelets and coagulation to give stabilising fibrin
fibrin generation?
fibrin forms a mesh at the injury site to stabilise the thrombus
formed as the endpoint of the coagulation pathway
when is the coagulation pathway activated?
during primary haemostasis
where are coagulation complexes formed?
on the negatively charged platelet membrane surfaces
- a complex series of protein-protein interactions
- lead to generation of thrombin from prothrombin
- blood/platelet-derived soluble fibrinogen cleaved to fibrin by thrombin (secondary haemostasis)
VWF?
very large protein
size of VWF?
forms multimers of 80 subunits >20,000 kDa
where is VWF present?
present in plasma, platelet granules, storage granules in endothelial cells (Weilbel Palade bodies) and also bound to some ECM protiens)
describe VWF in resting conditions?
VWF is globular and does not bind to platelets
what can cause VWF to unfold? and what does this expose?
high shear stress or collagen binding causes VWF to unfold which exposes platelets binding sites
von willerband disease reported in which animals?
cats (rarer), rabbits, cattle, horses and pigs
von willerband disease in dogs?
most common inherited platelet defect in dogs
what is Von Willerband disease caused by?
Caused by VVWF production
type 1 von willerband disease?
most common
clinically mild/moderate, low VWF concentration, normal multimer formation
type 2 von willerband disease?
clinically moderate/severe, low VWF, loss of high MW multimers
DIC?
disseminated intravascular coagulation
always secondary to a primary disorder
sepsis is a massive cause
what does DIC do?
lots of tiny clots throughout circulation
sequesters all platelets
lack of coagulation factors
so you get bleeding and thrombosis at same time
no way to stop bleeding but also need to remove clots
type 3 von willerband disease?
clinically severe
total absence of VWF
which is the less common type of von willerbrand disease?
autosomal recessive
which is the more common version of von willerbrand disease?
autosomal dominant with incomplete penetrance
treating von willerbrand disease?
no cure but can be treated
in which dog breeds is von willerbrand disease relatively common in?
Doberman Pinschers, German Shepherds, Golden Retrievers, Miniature Schnauzers, Pembroke Welsh Corgis, Shetland Sheepdogs, Basset Hounds, Scottish Terriers, Standard Poodles, and Standard Manchester Terrier
what is a thrombosis?
an inappropriate clot formation in vessels without vascular injury
leads to: myocardial infarction and stroke
what is an arterial thrombosis?
atherosclerosis plaque rupture or immune stimulus
what is a venous thrombosis?
a DVT
how does cancer lead to a thrombosis?
hyperactivation of platelets, weak blood vessels, involvement of coagulation factors
if thrombosis results in sepsis, what can this lead to?
DIC
disseminated intravascular coagulation
thrombosis can also lead to? an example is COVID
can lead to viral activation
what are the primary disorders that DIC can be secondary to?
sepsis, cancers, pancreatitis, heartworm disease, toxoplasmosis, gastric dilation-volvulus, immune conditions - immuen mediated haemolytic anaemia or thrombocytopenia, snake/insect bites, heat stroke, septic peritonitis
what does DIC result in?
in systematic microvascular thrombosis, ischaemia and organ failure
what happens in DIC?
small clots use up platelets and coagulation factors causing serious bleeding
what does VWF act like and in order to do what?
acts like a fishing line ‘snagging’ passing platelets
haemostasis is a balancing act - what does haemostasis need to be in order to keep it balanced?
sensitive, rapid, localised, stable, coordinated, controlled
describe how haemostasis can be in balance?
procoagulant forces and anticoagulant forces are level with each other
what happens to the haemostasis balance when we are bleeding?
There is a haemostasis disbalance anticoagulant forces are stronger than procoagulant forces
the anticoagulant forces outweigh the procoagulant forces
describe the haemostasis balance when there is a thrombosis?
Haemostasis disbalance
the procoagulant forces outweigh the anticoagulant forces
unsettling the haemostasis balance will cause what?
it will either result in inappropriate clotting (thrombosis)
what does VWF stand for?
Von Willerbrand Factor
rapid -
thrombus appears in seconds
localised -
limited to injury and compacts so no occlusion
stable -
doesn’t have lots of chunks embolising
coordinated -
rapid activation of platelets and coagulation to give stabilising fibrin
Describe platelet activation - 1?
platelets have adhesion receptors on their surface
receptors recognise components of ECM incl. GPCR, Integrins, Glycoproteins/Ig superfamily
Initial interactions (between receptors and ECM) mediated through collagen and VWF
Binding of platelets to ECM starts activation through signalling cascades
Activation causes granule secretion
Describe platelet activation - 2?
Granule contents support further platelet activation
Granular fibrinogen supports platelet aggregation
Granular P-selectin supports interaction between platelets + WBC
Platelets change shape and spread over wound
Changes in phospholipid composition
Exposure of PS gives a negatively charged surface
Charged surface promotes the assembly of coagulation cascades
leads to thrombin generation
thrombin cleaves fibrinogen to fibrin
fibrin stabilises the clot
what two molecules help when granule contents support further platelet activation?
ADP and VWF
what does PS stand for?
phosphatidylserine
what does PS do?
exposure of PS gives a negatively charged surface
many severe diseases involve thrombocytopenia - what are these diseases?
infections
neoplasia (cancers)
immune disorders
pancreatitis
drugs e.g. chemotherapy or antibiotics
signs of thrombocytopenia?
nosebleeds, gum bleeds, bleeding under the skin
thrombocytopenia can affect both?
both cats and dogs
what is hereditary macrothrombocytopenia?
it is a benign inherited giant platelet disorder
who does hereditary macrothrombocytopenia affect?
affects 50% Cavalier King Charles Spaniels
what do platelets use receptors for?
to sense proteins that are only exposed during vascular injury
what proteins do platelets sense with their receptors?
collagens found in the extracellular matrix
and
Von Willebrand Factor (VWF) in blood can then bind collagen and bridge the platelet the ECM
activated, adhered platelets expose what?
they expose a surface that is procoagulant
exposure of a procoagulant surface allows what?
allows assembly of coagulation complexes
leads to local generation of thrombin
receptor for this activation normally anatomically sequestered from blood (TF)
meaning of ECM?
extracellular matrix
unperturbed meaning?
unphased - not unsettled
what does unperturbed endothelium present?
it presents an anticoagulant response to prevent inappropriate activation of coagulation
what does an anticoagulant response limit?
limits the spread of the clot (thrombus) beyond the injury site to prevent vessel occlusion
