Haemorrhage, Homeostasis, Coag, Thromb Flashcards
PART I…
I. Haemorrhage
What is a haemorrhage?
bleeding from a ruptured blood vessel
What is haemostasis?
the stopping of bleeding
What is thrombosis?
formation of a clot inside a blood vessel
When is thrombosis beneficial?
in the case of trauma/injury to stop bleeding
When is thrombosis detrimental?
in DCT or other pathological conditions
What types of drugs inhibit detrimental thrombosis?
anti-thrombotic drugs
What are the 2 types of haemorrhage?
- internal: leaky blood vessels inside body
- external: natural opening/break in skin
What are 2 causes of haemorrhage?
- trauma: different types of injury
- medical condition: intravascular, intramural, extravascular
What is meant by the medical conditions capable of causing a haemorrhage:
- intravascular
- intramural
- extravascular
- defects in the blood
- defects in the vessel wall
- defects outside blood vessels
What are 6 risk factors for a haemorrhage?
- congential (haemophilia)
- medication (anti-coagulants)
- age (poorly tolerated by elderly)
- trauma (burns/punctures/ballistic)
- disease (liver disease
- infection (gastroenteritis)
What are the 4 classes of haemorrhage according to the American College of Surgeons database?
- class I
- class II
- class III
- class IV
What are the characteristics of a class I haemorrhage (loss percentage of blood volume, vital signs)?
- loss of <15% blood volume
- no change in vital signs
What are the characteristics of a class II haemorrhage (loss percentage of blood volume, vital signs)?
- loss of 15-30% blood volume
- tachycardia, vasoconstriction
What are the characteristics of a class III haemorrhage (loss percentage of blood volume, vital signs)?
- loss of 30-40% blood volume
- ↓ BP, ↑ HR, shock, confusion
- volume expander or transfusion necessary
What are the characteristics of a class IV haemorrhage (loss percentage of blood volume, vital signs)?
- loss of >40% blood volume
- limit of body’s compensation mechanisms, possible death
- aggressive resuscitation required
most severe
Haemorrhage grading scle of bleeding?
0: no bleeding 1 2: sometimes clinically significant 3: severe 4: possible death- too much blood lost
What is observed with haemorrhagic shock? (3)
- hypovolemia (decreased blood volume)
- reduced cardiac output
- reduced organ perfusion
What are the physiological/clinical responses to stop further blood loss in a haemorrhage?
- vasoconstriction (req mechanical pressure)
- haemostasis/thrombosis (amplified by haemostatic agents)
- fibrinolysis (dissolution of blood of clots - antifibrinolytic agents)
- surgery (to inhibit bleeding)
What are the physiological/clinical responses to replace lost blood volume in a haemorrhage?
- volume expanders containing crystalloids (aqueous sols of mineral salts + other water-soluble molecules) and colloids (containing larger insoluble molecules like gelatine)
- blood transfusion
II. compensatory mechanisms
III. haemostatic agents
What is the body’s first reaction to a haemorrhage?
Activation of compensatory mechanisms that regulate blood loss to restore haemostasis
What is the first consequence of blood loss that can activate compensatory mechanisms for a haemorrhage?
- ⬇ arterial pressure
- altered blood gases
activate baroreceptor reflex + chemoreceptor reflex respectively
= cardiac stim, systemic vasoconstr, flow+vol redistribution
What is the kidney’s trigger to activate compensatory mechanisms for a haemorrhage?
RAAS activation (kidneys, adrenal, liver, lungs)
What is the pituitary’s trigger to activate compensatory mechanisms for a haemorrhage?
vasopressin (ADH) release
What is the sympathetic nerves’ trigger to activate compensatory mechanisms for a haemorrhage?
catecholamine release (sympathetic nerves, adrenal)
RAAS system diagram p89 and 90…
What are the two main aims of the body when responding to a haemorrhage?
- increase blood pressure
- increase blood volume
What are the two ways the body increases blood pressure?
- vasoconstriction
- tachycardia
What are 3 mechanisms resulting in vasoconstriction to increase BP in response a haemorrhage? (hint: think about the kidney’s, sympathetic nerves’ and pituitary triggers)
- AngII formation – ↓ BP → ↑renin (kidney) → ↑Ang II
- baroreceptor reflex - ↓ BP → ↑NAd (sympathetic nerves) tachycardia
- vasopressin (ADH) - ↓ blood volume → antidiuretic effect
What are the four ways the body increases blood volume?
- vasopressin baroreceptor reflex (⬇ water excretion + thirst)
- Ang II formation (↑vasopressin → ↑aldosterone.. antidiuretic effect)
- aldosterone
(Na+ and water retention) - erythropoietin production - ↓O2 (kidney) → ↑Epo → ↑erythrocytes
What is the prognosis of a haemorrhage (3 peaks of death)?
- minutes: exsanguination (severe blood loss)
- hours: progressive decompensation (due to failure of compensation mechanisms)
- days-weeks: sepsis and organ failure
signs and symptoms - haemorrhage?
tachycardia
rapid breathing, ⬇ pulse pressure, pale, anxiety
⬇ systolic pressure, confusion, agitation
loss peripheral pulses, ⬇ urine, loss of consciousness
what may some symptoms of haemorrhage be masked by?
use of drugs- b blockers
.. inhib effects e.g. tachycardia
Blood loss reduction summary diagram
page95
III. haemostatic agents
What are 3 haemstatic agents?
- Recombinant factor VIIa (FVIIa)
- desmopressin (DDAVP)
- fibrinogen
how does recombinant factor 7a VIIa (FVIIa) work?
⬆ formation of factors IXa and Xa
to ⬆ thrombin generation and fibrin formation
What is desmopressin (DDAVP) an analogue of?
vasopressin
What does desmopressin (DDAVP) stimulate the release of? How does it do this?
release of VWF from endothelial cells by acting on V2 receptor
-> results in a secondary increase in factor VIII levels
What does DDAVP increase?
fibrin formation and platelet deposition
What does fibrinogen enhance the formation of?
fibrin
What are 3 antifibrinolytic agents?
- tranexamic acid (TXA)
- epsilon aminocaproic acid (EACA)
- aprotinin (Trasylol)
What are TXA (tranexamic acid) and EACA
and what do they inhibit the conversion of?
affect?
synthetic lysine analogues.
:plasminogen to plasmin
= ⬇ fibrinolysis -> ⬆ clot stability
What type of inhibitor is aprotinin (trasylol)? What does it inhibit
- serine protease inhibitor
- inhibits plasmin
What does aprotinin (trasylol) reduce?
fibrinolysis, leading to an increased clot stability
same as EACA and TXA
PART II…
I. Haemostasis: primary and coagulation
major components of haemostasis- stages?
vasc injury… collagen-> platelet formn
tissue factor-> coagulation cascade
primary haemostasis: platelet plu
secondary haemostasis: blood clot from fibrin
plasmin
–> finbinolysis+ clot degradation
pic on p101
Primary hemostasis occurs at the site of vascular injury. What happens in primary hemostasis?
weak platelet plug formed due to vasoconstriction and platelet activation to limit blood loss
What happens in secondary hemostasis?
Activation of coagulation cascade in plasma generates thrombin.
Thrombin converts fibrinogen to fibrin which then polymerizes.
Fibrin strands strengthen the primary hemostatic plug.
Name platelet activator and platelet inhibitor?
activator
- collagen
- thrombin
- fibrinogen
inhibitor
- nitric oxide
- PGI2
what 2 things form a thrombus/blood clot?
platelets-haem plug from primary
+
fibrin- clot coagulation, from secondary
what are platelets?
v reactive blood cells…
after agonist, theyre activated
in which state are platelets unable to react with fibrinogen?
resting state
What is the difference between activated and resting state platelets?
resting shape: discoid and granular with inactive integrins.
Activated have different shape, degranulated and integrin activated
what can activated platelets do?
aggregation
adhesion
spreading on endothelium surface
procoagulant
3 steps to forming a platelet plug? to recruit to sit?
p105
- transloacation
- signalling inside platelets, secrete molecules, allow… - adhesion to sub endothelium
- aggregation- after recruiting others.
= thrombus formation (after binding w fibrinogen molecule and bridging platelets)
what factor on a platelet is important for aggregation and when is it inactive?
integrin aIIbb3
inactive on resting platelet… thus cant interact w fibrinogen for aggregaton
when are granules secreted from platelets?
after activation
thrombin= activates platelets, what can the integrin aIIbb3 now do?
converted into active form, can bind fibrinogen and bridge to platelets together
= form a platelet plug!!
what 2 types of granules are found within resting platelet?
dense granules
alpha granules
after activation, theyre released
name some alpha granules found within a resting platelet
coagulation factors P-selectin for immune response anti-bac angiogenic chemo-attractants
name some dense granules found within a resting platelet
ADP: mojor sec mediator for platelet activation Ca2+ serotonin CD63 LAMP1/2
what do platelets do once activated? w granules and generating something…
ADP released from dense granules generate TxA2 (Thromboxabe A2)
= ADP and TxA2 = 2 sec mediators of platelet activation
what are the 2 sec mediators of platelet activation and when are they released and where?
once platelet activated…
to autocrine pathway, platelet activation, at + feedback loop
(as ADP will go sit in another resting platelet)
what do anti platelet drugs target?
ADP and TxA2 = the 2 sec mediators of platelet activation…
= target amplification loop of platelet activation and not first initial steps of platelet activation
classical haemostasis is XX dependant?
GPIIbIIIa (aIIbb3)
summary of 3 steps of classical haemostasis
- rolling
at site of vasc injury
dependant on GPIb interaction w prothrombin? factor - Activation
platelets firmly adhere, secrete molecules in thrombin, ADP, TxA2 (sec mediators) recruit other platelets, form pluf - stable adhesion, thrombus growth
plug must be solidified by fibrin and activation of coagulation- allow stabilation of clots ☺
sec haemostasis: coagulation happens at site of tissue damage/injury …
main aim of coagulation=?
generate thrombin (enzyme that gen by coag cascade. fibrinogen-> fibrin clot... allow integration and stabilation of clot) ☺
what may inc risk of embolism and bleeding? (sec haemostasis: coagulation)
any defects in fibrin generation from fibrinogen… cant form clot
thrombus formed not stable! :(
what 3 things may thrombin do other than help form fibrin clot in coagulation cascade?
- amplify coagulation cascade
- vasoconstriction (directly)
- platelet activation
thrombin= key thing in reg of whole process of haemostasis!!
what are the 2 pathways to generate thrombin?
when activated?
intrinsic: activated on polyanions surfaces (tissue damage) not activated in healthy donors. mainly infection as bacteria can activate. stents, heart disease…
extrinsic: site of injury
What is the common phase between the intrinsic and extrinsic pathway leading to the formation of a fibrin clot?
converge to activation of factor Xa which cleaves prothrombin (II) -> thrombin (IIa) (key molecule of coag) then this changes fibrinogen -> fibrin-> form blood clot
what form are all the coagulation factors in, in intrinsic pathway of thrombin formation?
inactive, and can be activated by: A/ same factor in active form.
cascade effect as XIIa activates XI, XIa activates IX…
hows extrinsic pathway activated?
exposure of TF (tissue factor) in sub-endothelium, and gets upregulated in endothelial cells-> can bind to factor VIIa
TF: VIIa changes X-> Xa
what do TF: VIIa and IXa factors have in common?
TF: VIIa is in extrinsic pathway
and IXa in in intrinsic
both change factor X to XA which converges into common pathway and converts prothrombin to thrombin -> fibrinogen to fibrin… form fibrin clot ☺
central role of thrombin in coagulation- what are the 3 phases?
- initiation: exposure of TF, little thrombin formed (NOT enough to support fibrin gener, but enough to….
- amplification: of coag cascade and activate others… burst of thrombin and propagation
- propogation: lot of thrombin, can now gen fibrin and XIII, TAFI, enough to cross link fibrin and stabilise it
prothrombotic activity of platelets: wheres PS (phosphatidylserine) uaully located and role?
inside of inner memb of platelet surface
platelet activated, PS exposed, allows assembly of coag factors on surface: Xa enzyme, cofactor Va and Ca2+
= prothrombinase complex
what does activation of prothrombinase complex from PS allow?
inactive zymogen: prothrombin –> active serine protease: Thrombin
PS complex… what will thrombin formation from prothrombin allow?
thrombin: convert
fibrinogen-> fibrin polymers
3 potential pathways involved in change form prothrombin -> thrombin?
intrinsic pathway: X->Xa
extrinsic pathway: X->Xa
then… Va, PS, Ca2+, Xa = prothr-> thrombin
whys generation of thrombin a positive feedback loop?
can go back and generate other coag factors on diagram… make more thrombin
= amplify its own generation
little platelet= make lots of thrombin
how will thrombin also trigger negative feedback loop? that will limit formation + coag cascade
gen thrombin binds to thrombomodulin (receptor on endothelial cells), complex will activate powerful anticoag pathway APC.
APC (activated protein C) inhib co factors of coag: 8 and 5.
powerful!!
limits!!
after coag cascade triggeres, what system used to limit?
natural anti coagulant system
3 natural anti coagulant system?
- activation of TFPI
- Anti thrombin AI
- APC (most powerful)
hows natural anti coagulant system: APC (most powerful one) generated?
thrombin binding to thrombomodulin…
transforms PC-> APC
inhibit co factors Va and VIIIa
2 stages of haemostasis?
summary in detail
primary hemostasis (platelet plus) - platelets activated, secrete sec med: ADP, TAx2, recruit others to form plug. not stable. needs....
sec haemostasis: coag cascade
- 3 phases: initiation with bit of thrombin, amplification, propogate= thrombin burst…
gen fibrin.-> deposits on platelet plug, stabilise clot formation
clot formed, bleeding stopped
II. fibrinolysis
what is it?
degradation of a fibrin clot
fibrinolysis cascade formed by?
cleavage of plasminogen-> plasmin… which degrades fibrin into small pieces (FDPs)
resolve clot
how can fibrinolysis be inhibited?
factors formed by thrombin:
TAFI -> TAFIa
inhib/block fibrin degradation of the clot!
aim of fibrinolytic system?
limit clot growth- by degrading the fibrin
key protease formed in fibrinolysis and how activated?
plasmin (from plasminogen- inactive form is zymogen)
activated by tPA and uPA from kidney
plasmin can now degrade fibrin- degrade clot ☺
3 main pathways to inhibit the coag pathway?
TFPI (TF-> X)
antithrombin (X -> Xa)
APC (VIIIa, Va)
3 main pathways to inhibit the fibrinolytic pathway?
and what they each inhibit
PAI-1: tPA
a2 antiplasmin: plasmin
TAFIa: plasmin
how does TAFIa reduce fibrin clot degradation? detail pathway
thrombin made, neg feedback loop
binds to thrombomodulin…
activate TAFI into active TAFIa
inhib clot degradation by inhib plasminogen formation to plasmin (fibrin clot + plasminogen)
= inc clot stability
Anticoagulant, antithrombotic drugs
PART I…
Antiplatelets, anticoag drugs
what is an embolus?
‘stopper’
detached blood clot
whats coagulation
and role of anticoagulants?
process by which blood-> solid
AC: prevent blood from clotting… no affect on platelets/ fibrinolysis
what does antithrombotic do?
prevent thrombus (clot) from forming
whats a thrombolytic?
clot buster
drug that dissolves blood clots
platelet adhesion and activation more valid in what system?
arterial (not venous)
what stage of haemostasis do antiplatelets target?
primary haemostasis- platelet plug
what stage of haemostasis do anticoagulants target?
secondary: coagulation cascade
reduce fibrin and thrombin generation
what stage of haemostasis do thrombolytics target?
final:clot stabilisation
dissolve thrombi by degrading fibrin by increasing fibrinolysis
what 2 things can be targetted when targetting (reducing) thrombosis via drugs?
coagulation: fibrin clot
platelets: haem plug rish in platelets
–> both form thrombus/ blood clot
reducing fibrin… destroy clot bc not stable and solidified (bricks and mortar!!) need both fibrin + platelets
why may we differ between treating clot w antiplatelets/ anticoagulants
as some drugs rich in platelets… and some in fibrin
what plays a critical role in arterial system?
and what type of system is this?
HIGH shear system
platelets (thrombi rich in)
What is the difference between red and white thrombi?
red thrombi: RBC and fibrin
white thrombi: platelets
What is the difference between the treatment of white and red thrombi?
white thrombi is treated with anti platelets:aspirin and clopidogrel.
red thrombi is treated with anti coagulants: heparin and warfarin
what system has white thrombi and why?
arterial
as predom platelets
what system has red thrombi and why?
venous
as predom RBC
What are the 3 factors of virchows triad that contribute to thrombosis?
blood flow: immobile, AF
endothelial injury: trauma, atherosclerosis
hypercoagulation: inherited preg meds
when is thrombosis:
- good
- bad
stops bleeding: at site of vasc injury, forms clot
must be transient and non-occlusive
blocks blood supply, at site of vasc aterosc injury- arteries!
chronic, occlusive, embolise
where are bad thrombi: blocks blood supply, usually formed?
how treates?
in arteries, at site of atherosclerotic plaques.
use antiplatelet drugs to treat
what does high shear rate of arterial system allow?
platelets to interact w exposed cell endothelium at site of injury w collagen,
esp VWF and GPIb
allows platelets to roll on VWF and get activated… secrete sec mediators: ADP, TXA2 = form WHITE thrombi. platelets.
aim: ⬇ platelet activation and use antiplatelets to ⬇ thrombosis
why anticoags not used to treat arterial thrombosis?
as thrombi not rich in fibrin
most common antiplatelet: COX inhibitors- example and MoA?
aspirin. blocks cyclooxygenase (COX) inhib formation of TxA2 from arachidonic acid
common antiplatelet: P2Y12 inhibitors- examples and MoA?
clopidogrel, prasugrel, ticagrelor, cangrelor
block ADP receptor (second mediator of platelet activation)= reduction
antiplatelet: Phosphodiesterase inhibitors- examples and MoA?
dipyridamole
cilostazol
trifusal
block platelet activation+ aggregation…
stop cAMP –> 5’AMP
how do aIIbb3 inhibitors (antiplatelets) work?
e.g. abciximab
inhib platelet aggregation by inhibitiing interaction of platelets with fibrinogen
Name an antiplatelet drug that is an antagonist for alpha II beta 3 and is a monoclonal antibody?
abciximab
integrillin is an example of an alpha II beta 3 receptor blocker. Why were these trials stopped?
lack of efficacy and increased mortality due to risk of excessive bleeding
were restricted for use in acute hospital care- unstable angina..
snake venom peptide analogue
which two drugs are excellent anti thrombotic drugs and block secondary mediator activation and amplification loop of platelets?
aspirin: block COX, stop-> TxA2
clopidogrel: block P2Y12 rec for ADP
Aspirin has an irreversible effect for around the same life as a platelet half life. What length of time is this?
approx 10 days
Two things that aspirin and clopidogrel inhibit the action of?
TxA2 and ADP (receptor) positive feedback mediators
what venous thrombosis mainly mediated by?
(hows it diff to arterial)
what does this allow?
by turbulent shear- observed at level of valve in veins
allows coag cascade and RED thrombus formn (RBC + fibrin)
another way to reduce clots in venous system (and arterial)
increaase fibrinolysis... inc tPA, uPA (from kidneys)... inc plasmin gen and fibrin degradation into small peptides
thrombin activates TAFIa- inhib fibrinolysis by inhib fibrin degradation..
balance in pro and anti coagulant activated
how can natural pathways of coagulation be used as drugs to inhib coagulation
drug targets: 4 classes? anticoags
heparins: UFH/LMWH
Vit K antagonists
direct thrombin inhibitors
Factor Xa inhibitors
What is the first line drug class of choice to increase venous thrombosis?
anticoagulants
What degrades fibrin clots?
plasmin
what coag factors will be targetted by: Vit K antagonists?
vitK dependant coagulation factors: VII (7) IX (9) X (10) II (2)
what coag factors will be targetted by: Heparins: LMW/UFH?
Extrinsic: VIIa (7a) Intrinsic: XIIa (12a) XIa (11a) Xa (10a) IXa (9a) IIa (2a)
what coag factor will be targetted by: direct thrombin inhibitor?
IIa (2a)
antithrombin III is a v powerful inhibitor and also used as…
physiological suicide inhibitor
What does antithrombin III (serpin) do?
inhibits coagulation by inhibiting thrombin (binds to active site).. forms thrombin:AT complex (inactive)
first choice anti coag: heparin: role in antithrombin III MoA?
binds to AT (antithrombin), increasing efficacy 1000x, as cofactor… which binds to thrombin
doesnt act directly on thrombin but inc capacity to bind to AT and thrombin
What does heparin act as a co factor and bind to in order to inactivate thrombin?
antithrombin (serpin)
what type of anticoag is anti-thrombin?
broad as can also inhib other coag factors in cascade
What is the drug class of warfarin? (anticoagulants)
Vitamin K analogue.
inhib vitK dep factors II, VII, IX, X
warfarin MoA?
Warfarin competitively inhibits vitamin K epoxide reductase complex 1 (VKORC1), an essential enzyme for activating vitamin K available in body
…depletes functional vitamin K reserves and reduces synthesis of active clotting factors (II, VII, IX, X)
what enzyme converts inactive II, VII, IX, X into active form in liver (Vit K recycling) warfarin MoA role?
vit K-dependant carboxylase
warfarin indirectly inhibits
commonly used anti coag drug:
IIa inhibitors target only …
thrombin (IIa)
what heparin is more specific and what coag factors does it target?
LMW
XIa, IIa… 11a, 2a (thrombin)
what drug class are thrombin inhibitors and give examples of
- direct
- indirect
anticoags for venous thromb
- argatroban, dabigatran, desirudin
- enoxaparin, dalteparin, fondaparinux, UFH
4 examples of direct Xa inhibitors (anticoags)
apixaban, betrixaban, edoxaban, rivaroxaban
examples of thrombolytics
plasminogen activators
- reteplase
- streptokinase
- tenecteplase
- tissue plasminogen activator
inhib through inc fibrinolysis
PART II…
I. Thrombolytic agents
II. Anti thrombotic agents choice
aim of arterial thrombosis?
reduce pla activation by using antiplatelets
P2Y12 inhibs do what?
inhib ADP effect on platelets
The aim of thrombolytics is to activate another process to degrade fibrin clots. What is this process called?
fibrinolysis
The aim of thrombolytics is to activate another process to degrade fibrin clots. What is this process called?
fibrinolysis
why are thrombolytics not commonly used?
stroke
limited time to use, then inc risk of bleeding
How can the activation of fibrinolysis be reduced?
red factors/ haemostatic agents prevent plasmin generation
fibrinolytic system: whats the common agent used?
tPA (endothelial cells)… also have uPA (kidney)
what does tPA (fibrinolytic agent) do?
inc formn of plasmin from plasminogen…. –> fibrin degradation into fibrin.
haemostatic agents that inhibit fibrinolytic system by inhib plasmin?
transexamic acid
aminocaproid acid
commonly used thromolytics (clot busters)? + examples of each
recombinant tPA: alteplase, reteplase, tenecteplase
urokinase: abbokinase, kinlytic
streptokinase: sec by streptococci
List 5 indications for thrombolytics?
- acute stemi
- acute ischaemic stroke
- peripheral artery occlusion
- DVT
- PE
Is arterial thrombosis due to platelet rich thrombi or a fibrin rich clot?
platelet rich thrombi
Is arterial or venous thrombosis due to fibrin rich clots?
venous thrombosis
