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119 Cards in this Set

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  • Back
What are the three things involved in haemostasis?
The vessel wall
Coagulation phase
How does the vessel wall help in haemostasis?
It constricts (only locally ie it's focal) and signals that there's been damage
How does the vessel wall normally act as a non-stick surface / inhibit platelet adhesion? What does it produce to allow for this?
- Prostacyclin (PG12) = vasodilator and inhibits platelets
- NO = vasodilator
-t-PA = tissue plasminogen activator ie activates the conversion to plasmin -> break down any clots
- Also have ADPase (breaks down any ADP from platelets) and heparan sulfate on the surface on endo cells
How do platelets adhere to the vessel wall?
via vWF - it grabs them as they're whizzing by at high speed and acts as a bridge
Does vWF binding activate the platelets?
NO! Binding catches the platelet and holds it there. But other things activate it (eg THROMBIN!)
What changes occur once the platelet has been activated?
Granules move to surface and release their contents (importantly, ADP and TxA2)
The surface receptors are activated
The negatively charged phospholipid is externalised
What are the two types of granules in the platelet and what do they store?
Dense granules -> ADP, Ca2+ etc
Alpha granules -> coagulation factors, adhesion molecules etc
What is the structure of vWF?
It's produced as a dimer and then polymerises into very long polymers (becomes the longest protein in the body)
What are the two roles of vWF?
Act as a bridge between the subendothelial matrix and the platelet
Stabilise factor VIII
Why is the polymer structure of vWF so important?
allows it to grab the platelets when they're zooming past so fast
What cell type do platelets derive from?
How long do platelets last in the circulation?
5-7 days
What is the significance of the phospholipid membrane in the platelet?
it's normally internalised but when the platelet gets activated, it gets externalised --> coag factors will bind to the platelet now (requires Ca2+ to act as the 'bridge')
When a platelet degranulates, what are the two most important things it releases?
What do they do?
ADP and thromboxane A2
They recruit more platelets into the area and activate them
What is the special name given to the inactive form of coagulation factors?
What is the common pathway in the clotting cascade?
We have Xa from either of the two pathways
X + its cofactor V activate prothrombin to thrombin
Thrombin then activates fibrin from fibrinogen
How do we breakdown a clot?
What do we get produced when we break down a clot?
Fibrin degradation products (FDPs) eg D-dimers
What is the goal of the whole clotting cascade?
To generate fibrin (lots) to stabilise the platelet plug we've started forming
What is the other name of factor II?
What is factor X's cofactor?
What factors are synthesised in the liver?
The vitK dependent ones: II, VII, IX and X
as well as V, VIII and fibrinogen
What has to happen to factors II, VII, IX and X before they are active?
Need to be carboxylated!
The factors already have a glutamate rich tail. We need to convert the glutamate to gamma-carboxyl glutamic acid so the factor can anchor into the platelet membrane
Vitamin K is involved in this carboxylation step
What is the role of vitamin K in synthesis of II, VII, IX and X?
Required for the carboxylation step
ie we convert the glutamate tails on the factos to a gamma-carboxyl glutamic acid.
This is necessary so that we get anchoring of the factors into the platelet membrane
How does warfarin work?
It blocks the carboxylation process of the vitamin K dep factors -> they can't bind to the platelet
Where is vWF produced?
Endo cells and megakaryocytes
Does someone with low vWF have haemophilia?
They will have low levels of VIII (because vWF is important in stabilising it)
But they don't technically have haemophilia! Important difference!
A problem with vWF could be due to two main things going wrong. What are they
The production of vWF could be stuffed
Or it could be produced fine but it can't form large multimers -> can't do it's job of grabbing the platelets as they zoom past
When a clotting factor reaches the end of its life span, what happens?
The carbohydrate side chain and sialic acid residues are usually removed.
Then it gets cleared by the liver
What organ clears the old clotting factors?
The liver
What is the half life of factor VIII
About 12-18 hours
What is the half life of factor VII
4-6 hours
What is the half-life of prothrombin
72 hours
If you're giving someone fresh plasma, how long until the factor VII levels have dropped by half
4-6 hours
How often do we need to give VIII to haemophiliacs to maintain good levels
About twice daily
What does warfarin act on?
Vitamin K --> decreased levels of factors. And you will get a decreased level of FACTOR C
In the first few hours of taking warfarin, what is the net effect?
Impacts on both the coag factors and PROTEIN C
When you start on warfarin, the protein C levels drop BEFORE the coag factor levels. Hence, we have an increase in coagulability before we get adequate anti-coagulation (during this time, need to anti-coag them with other drugs eg heparin)
What is the role of protein C?
It's a natural anti-coagulant
It's dependent on vitamin K
How will warfarin change APTT and PT?
It will increase them both
What is the half life of unbound VIII?
What's its half life when it's bound to vWF?
2 hours unbound
12 hours when stabilised by vWF
What's deficient in haemophilia A?
What's deficient in haemophilia B (aka xmas disease)
What is the inheritance pattern of haemophilia A?
It's sex linked - transmitted on chromosome X ("X linked recessive")
If a mother is a carrier of haemophilia and she has a daughter, how will the daughter be affected and what are the chances?
Girl = XX - she will get one X from mum and one from dad. There's a 50% chance she'll get the mum's bad X (hence be a carrier)

IE 50% chance carrier, 50% totally fine
If a mother is a carrier of haemophilia and she has a son, how will the son be affected and what are the chances?
Boy = XY. He gets his Y from his dad and X from his mum -> if he gets the bad X will have disease, good X -> he's clear

IE 50% chance affected, 50% totally fine
What is the incidence of haemophilia B compared with A?
How do we define severe, moderate and mild haemophilia?
Severe = less than 1% of fVIII (ie one unit p/dL)
Moderate - 2-4% / u/dL
Mild - 5-30
What is the normal range of fVIII in the blood?
50-80 units / dL
What are the levels of fVIII in someone with severe haemophilia?
Less than 1% ie less than 1 unit p/ dL of blood
How many exons in the fVIII gene?
If you have haemophilia, what will you PT and APTT be compared with normal?
APTT increased, PT normal
What is the inheritance pattern of von willebrand's disease?
Autosomal doinant
What are the two possible causes of vWD?
You could have a quantitative or qualitative abnormality of vWF
What are the hallmark features of vWD?
Mucosal bleeding, excessive bleeding from wounds / traumaand occasional joint bleeds
What are the hallmark features of haemophilia?
Bleeding into joints.
If they're not treated properly, they get very quick joint deterioration
When diagnosing, how would you tell the difference between haemophilia A and B?
Coagulation factor assays
How do we diagnose vWD? (2)
Ristocetin co-factor test - measures the agglutination of normal platelets in the patient's plasma. If there's a problem with vWF, agglutination will take much longer
- Use antibodies to detect vWF
What is the ristocetin co-factor test? WHat's it used for?
Used to diagnose vWD
We mix the patient's plasma (containing their vWF) with normal healthy platelets and look at agglutination time
Agglutination won't happen as readily if their vWF is stuffed
What are some of the causes of acquired coagulation defects?
- Liver disease
- Malabsorption syndromes
- Circulating anti-coagulants
- Anti-coagulant overdose
Why does liver disease cause coagulation defect?
- Liver disease -> depletion of vitamin K
- They can't properly clear the old clotting factors from the circulation
- Portal hypertension and hypersplenism -> thrombocytopenia
What does DIC stand for?
disseminated intravascular coagulation
What is DIC?
We have massive consumption of the clotting factors in the body. This can lead to bleeding OR clotting
What are the two main types of things that can cause DIC?
Release of pro-coagulant material into the circulation (eg amniotic fluid embolism or metastatic malignancy) - these are by far the main two
Widespread vascular damage (sepsis or major trauma)
50% of DIC cases are due to one thing. What is it?
Obstetric complications -> amniotic fluid is released into the circulation
What is HITs?
Heparin INduced thrombocytopenia
It's due to antibodies directed against the heparin-platelet complex --> antibodies bind and activate the platelet --> increased clotting (and decrease in platelet count because they're all being activated)
What are the antibodies directed against in HITs?
The heparin-platelet complex
How many kids per 1000 are physically abused in australia?
9/1000 (actual incidence would probably be higher!)
How many cases of notified child abuse are substantiated?
What are some clues that might lead you to be suspicious of child abuse?
- History of repeated accidents
- Child goes to lots of diff hospitals / doctors
- Long delay between their injury and seeking treatment
- History is vague and/or variable
- Injury was unwitnessed
Ask: "is the injury compatible with both the history and the child's physical abilities?"
What is the legislation in NSW re medical practitioners reporting suspected child abuse?
They must report if they have "Reasonable grounds" to suspect child abuse
What is the difference in symptoms / presentation in someone with coagulation defect compared to someone with platelet problem?
Coagulation -> they will get the platelet plug starting to form but it won't be stabilised by fibrin -> deep haemorrhages, DELAYED post-traumatic/post-op bleeds
Problem with platelets -> they won't stop even the little bleeds -> lots of little bruises (petichiae) etc
What is the difference in the characteristics of a bleed due to platelet problems compared to coagulation disorders?
Platelet problems -> you'll get heaps of little bleeds because you'll never be able to plug the hole. Petechiae, eccyhmoses, mucocutaneous haemorrhage, will bleed DURING operation
Whereas coagulation -> you get the platelets there, but never get a very stable clot. Deep haemorrhage, palpable ecchymoses (the biggest type of bruise), DELAYED post-op / post-trauma bleeds
What are the three types of bruises?
- Petechiae (smallest)
- Purpura (middle)
- Ecchymoses (biggest)
What is the INR?
International Normalised Ratio. Looks at the PT! way of normalising it across all labs
Which pathway does the PT test?
The EXTRINSIC pathway (VII, X, V, II)
What sorts of things could prolong the PT?
Liver disease, vitamin K deficiency, warfarin
Which pathway does the APTT test?
What sorts of things prolong the APTT?
Heamophilias A and B, vWD, heparin, lupus anticoagulant
How do we do a PT?
Take a sample of the patient's blood, extract the plasma
Add TF to the plasma and look at how long it takes to clot
ie stimulating the intrinsic pathway
How do we do an APTT?
Take blood sample, extract their plasma
We add phospholipids to the plasma -> stimulating the EXTRINSIC pathway
What test do we use to monitor warfarin?
Warfarin -> vit K factors -> mostly intrinsic (think about VII as being the important one to measure when measuring the vitK factors) ie we use the PT
But it will also increase the APTT! ie still impacts the extrinsic pathway
What principle underlies a mixing coagulation test?
We use it to differentiate between clotting factor DEFICIENCIES and the presence of clotting factor INHIBITORS
We mix the plasma with normal plasma and the do the test (can do both PT and APTT) again. If they were just lacking a factor, we will get correction by mixing (because the machine can't pick up a problem below 50%)
If you don't get correction, we know they have an inhibitor
What will happen in a mixing coagulation test if they are deficient in a coagulation factor?
The PT / APTT would have been abnormal initially
But when we mix their plasma with good plasma, it will correct
What is the thrombin time?
Tests the final conversion of fibrinogen to fibrin
How do we test fibrinolysis?
Look for D-dimers - they are fibrin degradation production - increased levels of D-dimers indicates increased fibrin breakdown
What will happen to the PT, APTT and bleed time with warfarin treatment?
PT will be increased (we use PT to monitor warfarin activity)
But APTT will be increased as well!
Bleed time will be normal (becuase bleeding time just depends on platelets)
What will happen to the PT, APTT and bleed time with haemophilia?
The PT will be normal
APTT increased
Bleed time normal
What will happen to the PT, APTT and bleed time with vWD?
PT normal
APTT prolonged
Bleed time prolonged! Because the platelets can't stick to the endothelium as well
What will happen to the PT, APTT and bleed time with DIC?
All things involved are being consumed --> increased PT, APTT and bleeding time
What determines the severity and frequency of bleeds in someone with haemophilia A?
Their residual level of factor VIII
What is the normal level of factor VIII?
50-80 units p/dL
How can a woman have haemophilia? (2 reasons)
- Lyonisation ie one of her X chromosomes is inactivated
- Homozygous for the bad gene (rare)
According to Haldane's law, what percentage of haemophilia cases are 'de novo'? ie no history of it in their family?
1/3 !
How many exons in the factor VIII gene?
Where is factor VIII gene located
chromosome X
At the distal end of teh long arm (Xq28)
What sort of mutation is present in 45% of haemophilia A patients?
Large inversion in the RNA between exons 22 and 23
At what stage of pregnancy can you do chorionic villi sampling?
10-11 weeks gestation
At what stage of pregnancy can you do amniocentesis?
15-16 weeks
What platelet count is required to be diagnosed as thrombocytopenic?
Less than 150
What does ITP stand for?
immune thrombocytopenic purpura
What is ITP?
An autoimmune disorder - you have antibodies directed against your platelets -> the spleen will clear the platelets -> you get severe thrombocytopenia (the platelets are NOT activated by these antibodies!)
What will a vitamin K deficiency do to the PT / APTT?
WIll increase BOTH of them!
What are the two possible causes of DIC?
RElease of pro-coagulant material into the circulation OR widespread vascular damage
What happens as a result of DIC?
Increased risk of bleeding (because everything is being used up) but also have increased risk of clotting
What is HITs?
Heparin induced thrombocytopenia
Heparin binds to the platelet -> auto-antibodies recognise the platelet-heparin complex - this activates the platelets --> increased clotting and a decrease in the platelet count
What is the tenase complex?
What is the prothrombinase complex?
What is required so that the clotting factors can bind to platelet surface?
Their negatively charged glutamate tails need to be converted to gamma-carboxyl glutamic acid - this is more negatively charged -> anchors the factor into the membrane.
Vitmin K is required in this step (it's converted from normal vitamin K to vitamin K epoxide)
What does warfarin do?
Acts on vitamin K
Prevents it from being converted to the epoxide form. This step is required in the conversion of the glutamate to gamma-carboxyl glutamic acid on the coag factor
What factor breaks down thrombin?
What is protein C?
An important natural anti-coagulant - it blocks the co-factors (V and VIII)
What is Virchow's triad?
The three things that increase risk of clotting:
1. Static blood
2. Hypercoagulable state
3. Endothelial damage
In HITS, what is the antibody specifically against? What does the heparin bind to on the platelet?
Heparin binds to PF4 = platelet factor 4
The antibody is against his PF4-heparin complex
What are the two things that happen in HITS?
Antibody binds to heparin-platelet complex -> platelets are activated --> increased clotting and decreased platelet count
We have heparans (heparin degradation products) on endothelium -> PF4 attaches to these -> get antibodies against these as well --> endothelial damage -> release of TF --> even more clotting
How soon after starting heparin do we see HITS?
Usually about 5 days after
But will be faster if they have been on heparin before
What is the 'thrombin time?
We take their blood - add a small amount of exogenous thrombin and look at how quickly we get fibrin forming
What can increase the thrombin time?
Most commonly - heparin - it potentiates anti-thrombin --> we won't get quick conversion of fibrinogen to fibrin
Could also be due to DIC or a rare thing called dysfibrinogenaemia (ie your fibrinogen is dodgy)
How does heparin work?
It potentiates the action of anti-thrombin III
What is the double whammy that happens in HITS in terms of increased risk of thrombosis?
1. antibodies bind to platelets -> activation -> increased clotting (and thrombocytopenia)
2. heparans on surface of endo cells will bind PF4 as well -> antibodies bind here -> endo cell damage -> TF is released --> increased clotting!