CVR haemostasis and thrombosis Flashcards
what is haemostasis?
- the cellular and biochemical process that enables the specific and regulated cessation of bleeding in response to vascular insult
what is haemostasis for?
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
blood coagulation video
https://www.youtube.com/watch?v=FNVvQ788wzk
what is secondary haemostasis?
stablisations of the plug with fibrin
- > blood coagulation
- > stops blood loss
what is primary haemostasis?
formations of an unstable platelet plug
- > platelet adhesion
- > platelet aggregation
- –> limits blood loss + provides a surface for coagulation
what is fibrinolysis?
vessel repair and dissolution of clot
-> cell migration/proliferation & fibrinolysis
what must be balanced for normal haemostasis?
fibrinolytic factors & anticoag factors
vs
coagulant factors & platelets
reasons for lack of factors in coagulation cascade?
congenital and acquired causes for failed production
-> increased consumption/clearance
how does GlpIb bind platelets?
via VWF
how does GlpIa bind platelets?
directly
what does binding of platelet to GlpIb/GlpIa cause?
release of ADP and thromboxane
what is it called when you have low numbers of platelets?
thrombocytopenia
disorders of primary haemostasis - platelets
Causes of thrombocytopenia?
- bone marrow failure e.g. leukaemia, B12 deficiency
- Accelerated clearance e.g. Immune (Immune thrombocytopenic purpura), Disseminated intravascular coagulation
- platelets pooled and destroyed in an enlarged spleen
ITP explanation
antiplatelet ABs stick to sensitised platelet
- cleared by macrophages of reticulo-endothelial system in the spleen
reasons for impaired function of platelets (2)
- hereditary absence of glycoproteins or storage granules
- > very rare - acquired due to drugs e.g. aspirin, NSAIDs, clopidogrel (common)
what is observed in Glanzmann thrombothaenia?
absence of the GPIIb/IIIa receptor on platelets
what is observed in Bernard Soullier syndrome?
absence of GPIb receptors
what is storage pool disease?
disorders referring to reduction in the granular content of platelets (dense granules)
what drug class is widely used n the prevention and treatment of cardiovascular and cerebrovascular disease?
antiplatelet drugs
what is the mechanism of action of aspirin?
irreversibly blocks COX -> inhibits production of thromboxane A2
why isn’t prostacyclin production blocked by aspirin?
endothelial cells can still generate is
how longs do the effects of aspirin remain for?
7 days
how does clopidogrel work?
irreversibly blocks P2y12 (ADP receptor) on the platelet cell membrane
disorders of primary haemostasis - VWF
-> what can cause problems with VWF? (2)
- Hereditary decrease of quantity +/ function (common)
2. acquired due to AB (rare)
2 functions of VWF in haemostasis?
- binding to collagen and capturing platelets
2. stabilising factor VIII
what type of inheritance pattern is VWD?
autosomal
two types of VWD?
- deficiency of VWF
2. VWF with abnormal function
disorders of primary haemostasis - the vessel wall
- causes of issues with the vessel wall
- inherited (Rare) -> Hereditary Hemorrhagic Telangiectasia , Ehlers-danlos syndrome, other connective tissue disorders
- acquired -> steroids, ageing “senile purpura”, vasculitis, scurvy
clinical features of disorders of primary haemostasis?
bleeding features:
- immediate
- prolonged from cuts
- nose bleeds
- prolonged gum bleeding
- menorrhagia
- ecchymosis - spontaneous/easy
- prolonged bleeding after trauma/surgery
what causes petechiae?
bleeding under the skin
what happens when glass applied to purpura?
don’t blanch
when do you see petechiae?
in thrombocytopenia
what disease can severe VWD present like?
haemophilia
tests for disorders of primary haemostasis? (4)
- platelet count and morphology
- bleeding time
- assays of VWF
- clinical observation
what tests come back normal in VWD?
PT and APTT, except in more severe VWD where FVIII is low
treatment of abnormal haemostasis: for failure of production/function
- Replace missing factor/platelets e.g. VWF containing concentrates
- > prophylactic
- > therapeutic
treatment of abnormal haemostasis: for immune destruction
- immunosuprresion e.g. prednisolone
2. splenectomy for ITP
treatment of abnormal haemostasis: for increased consumption
- treat cause
2. replace as necessary
additional haemostatic treatments
- desmopressin -> 2-5 increase in VWF. Releases endogenous stores
- tranexamic acid
- fibrin glue/spray
- other approaches e.g. OCP for menorrhagia
who is desmopressin useful in treating?
mild disorder cases
what is the roles of coagulation (chemically)
to generate thrombin
-> this converts fibrinogen into fibrin
4 causes of coagulation factor deficiencies
hereditary
acquired
dilution
increased consumption
hereditary causes of disorders of coag?
- factor VIII/IX -> haemophilia A/B
acquired causes of disorders of coag?
- liver disease
2. Anticoagulant drugs (warfarin, DOACs)
dilution causes of disorders of coag?
blood transfusion (also acquired)
increased consumption causes of disorders of coag?
- acquired
1. DIC (common)
2. immune (ABs, rare)
DIC = Disseminated intravascular coagulation
what deficiency occurs in haemophilia A?
factor VIII deficiency
what deficiency occurs in haemophilia B?
factor IX deficiency
coagulation disorders which aren’t haemophilia are what?
rare
autosomal recessive
what does haemophilia do to fibrin?
unable to generate it -> no stabilisation of platelet plug
elbow hallmark of haemophilia?
haemarthrosis (bleeding into joints)
-> prophylactic replacement therapy in developed countries prevents development
what does chronic haemarthrosis lead to?
muscle wasting
what type of injection should be avoided in haemophilia?
intramuscular
-> leads to extensive haematoma
is the bleeding in haemophilia compatible with life?
yes
where do you see spontaneous bleeding in haemophilia?
the joints and muscles
what other factor (other than VIII and IX) can cause coag deficiences?
factor II (prothrombin)
is absence of prothrombin compatible with life?
no
what does factor XI deficiency lead to?
- bleed after trauma but not spontaneously
what does factor XII deficiency lead to?
- no change in bleeding
why does liver failure lead to acquired coagulation disorder?
- most coagulation factors are synthesised in the liver
why does dilution lead to acquired coagulation disorder?
- RBC transfusions no longer contain plasma
- major haemorrhage requires transfusion of plasma as well as red cells and platelets
what is disseminated intravascular coagulation?
- generalised not localised activation of coagulation tissue
problem with disseminated intravascular coagulation?
TF that normally doesn’t come into contact with factor VIIa binds to it and leads to widespread unregulated coagulation
what can trigger disseminated intravascular coagulation?
- sepsis
- major tissue damage e.g. cancer
- inflammation
what happens as a result of DIC to coag factors?
their widespread consumption and depletion
-> leads to thromboyctopenia
How can you test for DIC?
look for raised D dimer (breakdown product of fibrin)
what can deposition of fibrin cause?
- organ failure
2. shearing of the RBC in vessels its deposited in -> red cell fragmentation
how to treat DIC immediately?
give FFP and platelets (supportive treatment)
how to fix DIC?
treat underlying cause
clinical features of coagulation disorders (4)
- superficial cuts don’t bleed
- bruising common, nosebleeds rare
- spotaneous bleeding is deep; into muscles and joints
- bleeding after trauma may be delayed and is prolonged
disorders
pattern of bleeding in platelet/vasc vs coag?
p/v: superficial bleeding into skin + mucosal membranes
C: bleeding into deep muscles, muscles, joints
disorders
onset of bleeding in platelet/vasc vs coag?
p/v: immediately after injury
c: delayed but severe bleeding after injury. Bleeding is often prolonged
tests for coagulation disorders (3 types)
screening tests
coagulation factor assay
tests for inhibitors
screening tests for coag disorders:
PT
APTT
full blood count (platelets)
causes of prolonged APTT and PT (4)
- liver disease
- anticoagulant drugs
- DIC
- dilution following red cell transfusion
how to treat ITP
splenectomy
how to replace coagulation factors (4)
- FFP
- cryoprecipitate
- factor concentrates
- recombinant FVIII and FIX
what coag factors are in FFP?
all of them
what coag factors are in cryoprecipitate?
fibrinogen
FVII
VWF
FXIII
novel treatments for haemophilia
- gene therapy for A and B
2. bispecific antibodies for A
how do bispecific ABs treat haemophilia A?
binds FIXa and FX
mimics procoagulant function of FVII
How do disorders of thrombosis present (venous)? (2)
- PE
2. DVT
symptoms of PE (6)
- tachycardia
- hypoxia
- shortness of breath
- chest pain
- haemoptysis
- sudden death
symptoms of DVT (6)
- painful leg
- swelling
- red
- warm
- may embolise to lungs
- post thrombotic syndromes
2 examples of arterial thrombosis
- CVD
2. rupture of cholesterol-platelet-rich plaques
what is thrombosis?
intravascular inappropriate coagulation. Can be venous or arterial. Obstructs flow and may embolise to lungs.
virchows triad indicates what?
the 3 contributory faxctors to thrombosis
what is virchows triad?
- blood - dominant in VT
- vessel wall - dominant in AT
- blood flow - both AT and VT
what term refers to an increase risk of VT?
thrombophilia
features of thrombophilia
- young age thrombosis
- spontaneous thrombosis
- multiple thromboses
- thrombosis whilst anticoagulated
causes of thrombosis
- coagulant factors
2. platelets
factors that can be raised to cause thrombosis
- factor VIII
- Factor II
- factor V leiden
- myeloproliferative disorders
factor V leiden causes what?
increased activity due to activated protein C resistance
what anticoagulant proteins can be reduced to cause thrombosis?
- antithrombin
- protein C
- protein S
states that cause increase coagulation factors and platelets
- surgery
- cancer
- pregnancy
what is the cofactor of protein C
protein S
what does protein C do?
inactivate FVa and FVIIIa
what does anti-thrombin inactivate?
FIIa and FXa
is factor V leiden a high risk condition for thrombosis?
not necessarily. Tends to cause issues when accompanied by other risk factors e.g. pregnancy. OCP. long haul travel
order of significance of excess/deficiency for causing thrmobosis
- antithrombin deficiency
- protein C/S deficiency
- coagulation factor excess
what can inflammatory states alter expression of?
endothelial protein C receptor and thrombomodulin receptor
things that can cause blood flow stasis
- pregnancy
- long haul travel
- surgery
treatment of VT
prevention - prophylactic therapy + assess and prevent risks
reduce risk of recurrence/extension:
- lower procoagulant factors e.g. warfarin, DOACs
- increase anticoagulant activity e.g. heparin
what type of clots are most likely to grow and embolise
fresh ones -> need to focus treatment on these
which cells produce heparin?
mast cells
how are long chain - unfractionated - heparins given?
IV administration
how are LMW heparins given?
subcutaneous administration
action of unfractionated heparin
enhancement of antithrombin
-> inactivation of thrombin
-> inactivation FXa
(-> inactivation FIXa, FXIa, FXIIa)
why does LMW heparin have less in the way of antithrombin activity than long chain heparins?
wrap around antithrombin only, not FXa like the longer chains do
what does unfractionated heparin do to APTT?
prolongs it
Do we monitor APTT for LMWH heparin?
normally doesn’t require monitoring- doesn’t really affect APTT
If necessary measure anti-Xa levels to assess degree of anticoagulation
how does warfarin work as an anticoagulant?
blocks recycling of vitamin K
-> vita K dependent factors (II, VII, IX, X, protein C, protein S) not activated via gamma carboxylation
how can you reverse effects of warfarin?
vit K administration - takes hours
- rapidly reversed by infusion of coagulation factors e.g. by PCC or FFP
side effects of the anticoagulants?
- bleedings
- skin necrosis
- purple toe syndrome
- embryopathy = chondrodysplasia punctata
why can skin necrosis occur when on warfarin?
Due to severe protein c deficiency
Occurs 2/3 days after starting warfarin
-> thrombosis predominantly in adipose tissues
why can purple toe syndrome occur when on warfarin?
- disrupted atheromatous plaques bleed
- > cholesterol emboli lodge in extremeties
what is observed in chondrodysplasia punctata
- early fusion of epiphyses
2. warfarin is teratogenic in 1st trimester
what is used to monitor warfarin?
INR
unanticogulated normal INR is what?
1
target INR for warfarin patients
2-3
causes of warfarin resistance
- lack of compliamce
- diet with ++ vit K
- increased metabolism Cyt P450 (CYP2C9)
- reduced binding (VKORC1)
warfarin vs DOACS
onsent/offest
W: slow
D: rapid
warfarin vs DOACS
dosing
W: variable
D: fixed
warfarin vs DOACS
food effect
W: yes
D: no
warfarin vs DOACS
interactions
W: many
D: few
warfarin vs DOACS
monitoring required
W: yes
D: No
warfarin vs DOACS
renal dependence
W: No
D: some
warfarin vs DOACS
reversibility
W: vitamin K/PCCs
D: specific antidotes available for dabigatran and in development for FXa inhibitors
DOAC bleeding risk
- lower than for warfarin generally
- particularly for intracranial bleeding which is biggest worry
initial treatment of VT to minimise clot extension
DOAC/LMWH for first few days
-> follow with DOAC/warfarin
treatment to reduce risk of recurrence of VT
DOAC or warfarin
treatment for atrial fibrillation
DOAC/warfarin
treatment for mechanical prosthetic heart valve
warfarin
DOACs ineffective and should be avoided
thromboprophylaxis following surgery
LMWH or DOAC
thromboprophylaxis during pregnancy
LMWH -> DOACs not safe as they cross the placenta
