haemostasis Flashcards
what is haemostasis
cellular and biochemical process that enables both specific and regulated cessation of bleeding in response to vascular insult
what do we need haemostasis for
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
what is the first role of haemostasis in response to injury to endothelial cell lining
vessel constriction -
vascular smooth muscle cells contract locally
limits blood flow to injured vessel
what is primary haemostasis
formation of unstable platelet plug -
platelet adhesion
platelet aggregation
limits blood loss and provides surface for coagulation
what is secondary haemostasis
stabilisation of plug with fibrin
BLOOD COAGULATION
stops blood loss
what is last step - fibrinolysis
vessel repair and dissolution of clot
cell migration/proliferation and fibrinolysis
restores vessel integrity
why is it important to understand haemostatic mechanisms
- diagnose and treat bleeding disorders
- control bleeding in those without disorders
- identify risk factors for thrombosis
- treat thrombotic disorders
- monitor drugs used
what is the equilibrium in normal haemostasis
fibrinolytic factors and anticoagulant factors balance coagulant factors and platelets
what can cause a reduction in coagulation factors/plts
lack of specific factor - failure of production: -congenital and acquired -increased consumption/clearance OR defective function of specific factor - - genetic - acquired - drugs,synthetic defect,inhibition
what happens during platelet adhesion
damaged endothelial cells causes collagen to be exposed on surface
platelets can bid directly to collagen via glp1a or indirectly via glp1b to vwf
what does binding of platelets to collagen cause
release of adp and thromboxane
platelets are activated
what happens during platelet activation
glp2b/3a receptor on platelets is activated
what do we call low number of platelets
thrombocytopenia
what causes thrombocytopenia
- bone marrow failure e.g leukaemia,b12 deficiency
- accelerated clearance e.g immune(itp),disseminated intravascular coagulation (dic)
- pooling and destruction in enlarged spleen (splenomegaly)
what happens in immune thrombocytopenic purpura
itp
antiplatelet antibodies bind to sensitised platelet
these are then cleared by macrophages of the reticulo-endothelial system in spleen
what causes impaired function of platelets
- hereditary absence of glycoproteins /storage granules (rare)
- acquired due to drugs: aspirin,NSAIDs,clopidogrel (common)
what are some examples of hereditary platelet defects
Glanzmanns thrombasthenia
Bernard Soulier syndrome
storage pool disease
what are antiplatelet drugs commonly used for
prevention and treatment of cardiovascular and cerebrovascular disease
most common antiplatelet drugs
aspirin
clopidogrel
what is action of aspirin
irreversibly blocks cox enzyme results in reduced platelet aggregation
how many days does action of aspirin last for
7 days
platelets at time of aspirin ingestion are replaced by new platelets
what is action of clopidogrel
works by irreversibly blocking adp receptor p2y12, found on platelet cell membrane
what causes von willebrand disease
autosomal hereditary disease of quantity +/function (common)
acquired due to antibody (rare)
role of vwf
binding to collagen and capturing platelets
stabilising factor 8
what is type 1/3 vwd
deficiency in vwf
what is type 2 vwd
vwf with abnormal function
how can vessel wall cause disorder of primary heamostasis
inherited (rare)
hereditary haemorrhagic telangiectasia Ehlers Danlos syndrome and other connective tissue disorders
aquired (common): steroid therapy, age(senile purpura,), scurvy vit c def
how can steroids affect vessel walls in primary haemostasis
long term use can cause atrophy of collagen fibres that support vessels
how can scurvy( vit c def) affect vessel walls
defective collagen synthesis leading to weakening of capillary walls
summary of disorders of primary haemostasis
platelets: thrombocytopenia, drugs
VWD
vessel wall - hereditary vasc disorders, steroids,age,scurvy,vasculitis
what are some clinical features of disorders of primary haemostasis
immediate bleeding prolonged bleeding from cuts prolonged nose bleeding gum bleeding menorrhagia eccymosis - easy bruising prolonged bleeding after trauma/surgery
what is a sign of thrombocytopenia
petechiae -
small spots caused by bleeding under skin
<3mm
what is purpura
red/purple discoloured skin
- dont blanch when pressure applied
3-10 mm
how big does bleeding spot need to be for eccymosis
> 10 mm/cm?
how to test for disorders of primary haemostasis
platelet count/ morphology bleeding time - pfa100 now assays of vwf clinical observation coagulation screens pt and aptt is normal except severe vwd where f8 is low
normal range of platelet count
150 -400 x10^9/l
how to treat failure of production/function in abnormal haemostasis
replace missing factors/platelets e.g vwf containing concentrates
prophylactic
therapeutic
stop drugs e.g nsaids/aspirin
how to treat immune destruction in abnormal haemostasis
immunosuppression e.g prednisolone
splenectomy for itp
how can we treat increased consumption in abnormal haemostasis
treat cause
replace whats necessary
what are some additional treatments for abnormal haemostasis
desmopressin ddavp causes 2-5 fold of vwf
tranexamic acid - antifibrinolytic
fibrin glue/spray
other approaches e.g ocp for menorrhagia
what is the role of coagulation
generate thrombin (f2a) which converts fibrinogen to fibrin
what does the deficiency of any coagulation factor cause
failure of thrombin generation and hence fibrin formation
what causes deficiency of coagulation factor production
hereditary - f8/9 def : haemophilia a/b,
prothrombin def
f11,12 def
acquired - liver disease, anticoagulant drugs
what causes dilution in disorders of coagulation
acquired - blood transfusion
what causes increased consumption in disorders of coagulation
acquired - disseminated intravascular coagulation immune autoantibodies (rare)
what are the hereditary coagulation disorders
haemophilia a- f8 def
haemophilia b - f9 def
= sex linked
other are very rare - autosomal recessive
what was the hallmark of haemophilia
haemathrosis - bleeding in joint
long term can get muscle wasting
what does liver failure cause
reduction in coagulation factors as that where they are formed
what can disseminated intravascular coagulation be caused by
sepsis
cancer
obstetric disorders e.g pre eclampsia
associated with major tissue damage
what does unregulated coagulation in dic result in
widespread consumption and depletion of coag factors
thrombocytopenia
activation of fibrinolysis - raised d dimer
deposition of fibrin in vessels causing organ failure
what are the clinical features of coagulation factors
superficial cuts dont bleed
bruising is common, nosebleeds are rare
spontaneous bleeding is deep - into muscles and joints
bleeding after trauma is delayed and prolonged
bleeding frequently restarts after stopping
tests for coagulation disorders
screening test - clotting screen
pt,aptt,fbc
coagulation factors assays
test for inhibitors
what can be given for factor replacement therapy
ffp
cyroprecipitate
factor concentrates
recombinant forms of f8 and f9
what is found in ffp
contains all coagulation factors
what is in cyroprecipitate
rich in fibrinogen, f8,vwf,f13
what is found in factor concentrates
concentrates available for all factors except f5
prothrombin complex concentrates f2,7,9,10
novel treatments for haemophilia
gene therapy
bispecific antibodies - mimics procoagulant function of f8
rna silencing
what are some other factors that can increase bleeding
increase in fibrinolytic factors
increase in anticoagulant proteins
rare but induced by tpa or heparin
how does a pulmonary embolism present
tachycardia hypoxia shortness of reath chest pain haemoptysis sudden death
how does deep vein thrombosis present dvt
painful leg swelling red warm may embolise to lung post thrombotic syndrome
what is thrombosis
intravascular inappropriate coagulation
venous/arterial
obstructs flow
may embolise to lungs
what is virchows triad
3 contributory factors to thrombosis
blood - dominant in venous thrombosis
vessel wall - dominant in arterial thrombosis
blood flow - bith
what is thrombophilia
increased risk of venous thrombosis
how can thrombophilia present
thrombosis at young age
spontaneous
multiple thromboses
thrombosis while anticoagulated
what can cause venous thrombosis
reduction in anticoagulant factors - antithrombin, protein c, protein s
or increase in coagulant factors/ myeloproliferative disorders e.g increase in plts
when can reduced flow increase risk of thrombosis
pregnancy
long haul flight
how to prevent venous thrombosis
assess and prevent risks
prophylactic anticoagulant therapy
how to reduce risk of recurrence/extension of thrombosis
lower procoagulant factors e.g warfarin,DOACs
increase anticoagulant activity e.g heparin
what are some indications for anticoagulant treatment
venous thrombosis
atrial fibrillation
mechanical prosthetic heart valves
preventative too e.g following surgery, during hosp admission, pregnancy
what is heparin
naturally occurring glycosaminoglycans
produced by mast cells
porcine products used in uk
what is the action of unfractionated heparin
enhancement of antithrombin -
inactivation of thrombin - hep binds at and thrombin
action of lmwh
shorter polysaccharide chain
activity is predominantly against f10a
what is warfarin
vit k antagonist
f2,7,9,10, protein c and s are dependent on vitK
effective in vte and mi
why does warfarin require monitoring
has diff effects on diff individuals
many dietary, physiological and drug interaction
what are some effects of warfarin
bleeding
skin necrosis
purple toe syndrome
embryopathy - chondrodydplasia punctata
how to monitor warfarin
inr - international normalised ratio
standardised measure reflecting correction for diff thromboplastins
what can cause resistance to warfarin
lack of patient compliance - diet high in vit k
increased metabolism cytp450
examples of doacs
f10a inhibitors - rivaroxaban
apixaban
edoxaban
f2a inhibitor - dabigratan
compare doacs to warfarin
rapid fixed dosing no food effect few drug interactions as apposed to many in warfarin no monitoring required some renal dependance, none in warfarin
