M103 T2 L2 Flashcards
How is haemostasis prevented from spontaneously occuring in the body?
the endothelium secretes anticoagulants
What happens in the endothelium when it is injured?
it stops secreting anticoagulants and instead secretes VWF
What are the three platelet-based pathways to repair blood vessels? (PMV)
PHG, meshwork, vasoconstriction -- the formation of a primary haemostatic plug a meshwork on the clot via coagulation vasoconstriction to slow down blood flow
What three activities can platelets use to form a primary haemostatic plug?
(3As - dcg)
adhesion to the wall - exposed collagen in the basement membrane
activation - exocytose their dense granules
aggregation - the platelets stick together to start forming a plug
What is a clot made up of?
lots of little tiny fibres in every direction with cells stuck between them
What types of substances are released for vasoconstriction to occur?
the release of vasoconstrictors and coagulants
How many platelets is produced by one megakaryocyte?
on average 4000 platelets
What do platelets do when they’re activated?
exocytose - excrete various chemicals and vasoconstrictors
they change shape
increase in the amout of o2 they consume
What two terms are used to describe the two states of platelets?
quiescence - inactive / at rest - have smooth surfaces
pseudopodia - irregular shape / activated - have irregular surfaces
What three compounds are contained in the dense granules of platelets?
(SAC)
serotonin
ADP
calcium
What is the relationship between ADP and platelets?
ADP triggers platelet activation and stimulates aggregation
What are examples of blood thinners?
Prasugrel and Ticagrelor (antiplatelet agents)
Aspirin and Clopidogrel (anticoagulants)
What is the role of fibrinogen in clotting?
help the platelets bind to eachother and to the collagen
What substances are secreted during platelet activation?
ADP (activates the P2Y receptor)
TXA2
How does ADP use positive feedback to trigger platelet activation?
the ADP secretion will activate one platelet
when other platelets detect the ATP, they also activate
leads to positive feedback where more and more platelets activate
Are factors activated in the blood?
no, they mostly circulate in the form of inactive precursors so that reactions only happen when they need to rather than all the time
What special about factors 5 & 8?
they are co-factors not enzymes
How does tissue factor work?
when an individual cell is damaged, TF in the basement membrane underneath is exposed
it activates inactive clotting factors in the blood
How can atrial fibrillation cause a stroke?
the atrium is unable to pump successfully so blood just sits there
can form a thrombus which can travel to the brain
What two chemicals are added to blood to stop it from clotting in the lab?
citrate
heparin
What are the stages involved in coagulation?
fibrinogen (+ thrombin) > fibrin + factor 13 + Ca2+
causes cross links in the fibrin
forms a stable clot
Which two coagulation cascades are there?
the tissue factor pathway (ex)
the contact activation pathway (in)
What is thrombin activated by and how?
Factor Xa and Factor Va as a co-factor
How is Factor X activated?
by Xase from either the extrinsic or intrinsic pathway
How does positive feedback occur in coagulation?
thrombin activates Factor V & VIII into Factor Va and VIIIa
factor VIII contributes to Intrinsic Xase and factor V contributes to the thrombinase
essentially, it will activate thrombin itself, so thrombin activates upstream cofactors IOT activate itself
Which factors belong to the prothrombin group?
factors II, VII, IX and X
279,10
Which factors belong to the thrombin group?
Factors I, V and VIII
1, 5, 8
When will the amount of thrombin in circulation increase?
inflammation
pregnancy
with oral contraceptives
Where are clotting factors in the body?
made in the kidney
secreted into the blood
What is vitamin K’s function?
helps blot clot
required to synthesise various enzyme coagulation factors, in particular prothrombin
Which prothrombins require vitamin K to be synthesized?
2, 4, 5, 7
What happens if anticoagulant factors go into overdrive?
the inhibition of coagulation, fibrinolysis, accumulating blood vessel damage and eventual haemorrhaging
Where does plasmin come from and how does it activate?
inactive plasminogen, made as a plasma protein by the liver, activated by tPa
Where does protein C come from? and what is its function?
starts an inactive enzyme made by the liver
it is activated on surface of endothelial cells
What substance does antithrombin III work with and why?
always works with heparin
by itself, is very inactive / with heparin, powerful
What three substances does antithrombin III and heparin block from working?
thrombin
Factor Xa
Factor IXa
How can the effects of heparin be reversed in the lab?
protamine sulfate
What are the effects of an antithrombin III deficiency?
risk of thrombotic disease
What is the recombiant form of antithrombin III used for medically?
thrombotic disorders
What are the effects of a vitamin K deficiency?
reduced coagulation
What is a vitamin K deficiency usually caused by and how?
liver disease - it affects the production of bile salts so fat absorption can’t occur
AAR vitamin K can’t be produced by bacteria in the LI
What is haemophilia A caused by?
a congenital lack of factor VIII
Is haemophilia A more common in males or females?
Males - the condition is X-linked so with the exception of females who are homozygous for the mutated gene, only males show symptoms
How is haemophilia A treated?
injected forms of purified factor VIII - purified from an animal or blood products
it’s an expensive and rare medication
Why are the symptoms for haemophilia B the same as those for A?
haemophilia B involves a genetic defect in factor 9
Factors 8 & 9 are both part of the intrinsic pathway and work together to activate factor 10
How can purified factor VIII be generated in a cheaper way?
genetically modified animals’ milk
What is the positive feedback mechanism caused by atherogenesis?
monocytes / WBCs become foam cells
they can die and release their contents (cytokines and chemo-attractants - more signalling) which attract more monocytes
positive feedback mechanism
How does atherogenesis cause the reactivity of cholesterol esters?
lipids are deposited in lesions by LDL
the deposits can be made to be solid or hard by cholesterol esters in the lesion
the deposits can also be oxidized, making oxygen radicals
the cholesterol esters become so reactive that they can destroy any immune cells that try to regulate them
What three things is atherogenesis a disease of? (LIE)
lipids
inflammation
endothelium
What happens during atherogenesis to cause inflammation?
the endothelium expresses chemoattractants - they attract WBCs which allow monocytes to find and enter lesion
when the endothelium is lost, exposing the collagen basement layer, it stimulates coagulation
Endothelium normally covers collagen and basement membrane
when the endothelium is lost, the vessel can’t control its dilation - can’t control haemostasis
When are anti-platelet agents used instead of anticoagulants?
in acute coronary syndromes to prevent clotting in arteries where anticoagulants have limited effects
What are the uses of aspirin?
they are commonly used to reduce the risk of heart attack
acts as a blood thinner - is an antiplatelet agent
What are the medical uses of anti-coagulants?
prevent clotting in veins so it is prophylactic for DVT and PE’s
What are three examples of thrombolytics?
tPA
Streptokinase
Urokinase
What are three common anti-coagulants?
heparins
NOACs
Warfarin
What are the features of prothrombin Factors?
enzymes that need vitamin K for their synthesis and calcium for their activation
are stable
they all ultimately contribute to prothrombin synthesis
Why is platelet activation required for some coagulation steps of haemostasis?
bc the PPLPDs on the membrane are essential for driving some parts of the rest of haemostasis forward
How is vitamin K found in the body?
vitamin K has to be taken into the diet
What are the features of factors in the thrombin group?
activated by thrombin
V & VIII are co-factors - 5 works with 10 and 8 works with 9
Factor I is fibrinogen
What is the extrinsic pathway activated by?
external trauma
What is the overall effect of the extrinsic pathway?
it causes blood to escape from the vascular system
What is the difference between the extrinsic and intrinsic pathways?
extrinsic is quicker than intrinsic
intrinsic is more important than extrinsic
Why is it called extrinsic pathway?
because it is activated by TF, a protein extrinsic to the blood
What is the intrinsic pathway activated by?
by trauma inside the vascular system
by platelets, exposed endothelium or collagen
How does the intrinsic pathway work?
it amplifies the coagulation cascade via positive feedback
What is Extrinsic Xase a combination of?
tissue factor and factor 7a
What is Intrinsic Xase a combination of?
Factors 8a and 9a
Which factor is fibrinogen?
Factor I
What is the role of plasmin?
it dissolves the fibrin of blood clots
Where is Antithrombin III made?
in the liver
What is haemophilia B caused by?
a genetic defect in factor 9
causes a factor IX deficiency
What are antiplatelets otherwise known as?
anti coagulants
What is the use of fibrinolytics?
they dissolve fibrin in arterial disease - break clots
What are Fibrinolytics otherwise known as?
clot-busting drugs
thrombolytic agents
What key substance is produced by COX catalysation?
thromboxane
What is the physiological role of aspirin?
it blocks the formation of TXA2 in platelets
What substance do heparins work in co-operation with?
AT III
How are heparins administered?
injection into a vein or under the skin
What is the role of heparins?
they inhibit coagulation by inhibiting Factor Xa
What does NOAC stand for?
Novel Oral Anti-Coagulant
What are NOACs alternatives to?
warfarin
for high-risk patients who have atrial fibrillation
When is rivaroxaban used specifically?
DVT
PE
to prevent blood clots in atrial fibrillation
to prevent blood clots following hip or knee surgery
What substance does Rivaroxaban inhibit?
factor Xa
What terms are associated with warfarin?
anticoagulant
vitamin K antagonist
What is the onset of warfarin?
has a slow onset of 2 days and requires monitoring
How is warfarin administered?
injection
iv
orally - pills
What is the role of warfarin?
it prevents the recycling of vitamin K
to reduce clotting
What three substances are responsible for vasoconstriction?
Serotonin, ADP and TXA2
What are the two main types of blood thinners and how do they work?
anticoagulants - slow down the coagulation process of the body
antiplatelet agents - prevents platelet aggregation so they can’t develop into a clot
What is another term for warfarin?
Coumadin
How does Prasugrel work as an antiplatelet agent?
it inhibits ADP receptors
AAR, it inhibits the ADP-mediated platelet activation and aggregation occurs
How do Aspirin and Clopidogrel work as anticoagulants?
they slow the blood’s clotting action by making platelets less sticky
How does Ticagrelor work as an antiplatelet agent?
it blocks the P2Y12 receptor responsible for promoting platelets and blood clots
What is the function of protein C?
it inactivates Factor Va & Factor VIIIa
it works with a co-factor Protein S to inactivate Va
Why are vitamin K deficiencies rare?
bc vitamin K is made by bacteria in the LI
it’s also found in leafy green vegetables
How do WBCs become foam cells?
they enter a lesion and consume local cholesterol esters
What is nitrogen oxide’s relationship with inflammation?
in normal conditions it is anti-inflammatory
in abnormal conditions it is pro-inflammatory
