Lecture 11 - Thrombosis 2 Flashcards
What are two common inherited thrombophilias?
Factor V Leiden - Present in 3-5% Europeans, causes ~30% of venous thromboses
Prothrombin 20210G>A, 1-2% of Europeans, present in ~10-20% venous thromboses
Describe how Factor V Leiden increases thrombotic risk
Factor V Leiden is a mutant form of Factor V, and is present in ~30% of people with venous thrombosis.
It’s a single amino acid switch: arginine 506 to glutamine, and is autosomal dominant (homozygotes are more effected)
Protein Ca binds to and inhibits Factor V to inhibit coagulation, but when it binds to Factor VL it cannot break it down as quick, and so coagulation is not inhibited as quickly as normal (since Factor Va and Vllla persist for longer). It also means more protein C is occupied by breaking down FVL, meaning that less aPC is avaiable to breakdown normal FV and FVllla
The thrombotic risk for heterozygotes is mild: ~5-8x, whilst ~40x for homozygotes
How can you test for Factor V Leiden
Do a Activated Protein C (aPC) resistance assay
Can do a DNA test (but quite expensive) and normally done only to evaluate an abnormal screening test result
Describe the prothrombin 20210G>A mutation
It’s a promoter gene abnormality which results in causes more thrombin to be produced, resulting in increased thrombin concentration, which causes an increased thrombin burst - some thrombin may leave the site for injury and cause thrombosis elsewhere.
It creates a mild risk for venous thrombosis.
There is a 1-2% frequency of mutation in Caucasian population.
This creates a risk for venous thrombosis in pregnancy
What kind of conditions are Antithrombin, Protein C and S deficiencies?
All autosomal dominant conditions.
The thrombotic risk depends on the severity of the mutation affecting the protein.
Can can be done to assess the risk score for lower limb venous thrombosis?
- Wells score widely used to evaluate risk
- Laboratory data (evidence of recent fibirn production - this won’t work in patients with confounding problems, e.g. inflammation/surgery/trauma/childbirth
- Imaging studies
- Ultrasound/radiology
What can be done to confirm a high, moderate and low probablity Wells score?
High: Ultrasound, usually don’t perform D-dimer as it’s redundant
Moderate: Request D-dimer test (if no confounding), use ultrasound for confirmation
Low: Requuest D-dimer (if contraindications absent)
Use ultrasound only if D-dimer is contraindicated. If symptoms persist reassess after 2-3 days.
How can we assess the lungs of someone with a suspected pulmonary embolism?
V/Q scan: Ventilation perfusion scan.
- We can study their ventilation with isotope in air
- And we can do perfusion studies with isotope in blood
That pharmocologically based things can be done to prevent and treat thrombi?
- Anticoagulants
- fibrinolytic activators
- antiplatelet drugs
What type of thrombi should anticoagulants be used for, and which should anitplatelets be used for?
Anticoaglutants more effective at preventing venous thrombi and thromboembolisms, whereas antiplatelet drugs work better for arterial thombi and antiplatelet drugs
Just look at the slides for this lecture
In relation to warfarin treatment, when should UFH be used?
Should be used in short term treatment while warfarin is started. We need to give it by continuous IV infusion, monitoring it closely with APTT
When used prophylactically, how is UFH given?
Subcuntaneous (sc) low dose injection. The delayed absorption provides cover for up to 12 hours, these have largely been replaced by LMWHs which have a longer half life.
Main risks with UFH is HIT syndrome, leading to thrombocytopenia
How does LMWH differ from heparin?
LMWH has a reduced effect on anti-Flla (anti-thrombin) effect, so there is a slightly smaller risk of bleeding.
However LMWH retains it’s anti-FXa effect like normal heparin (this is its main anti-coagulation effect)
What enzyme does warfarin inhibit, and what does this result in?
Inhibits epoxide reductase, resulting in an inability of the epoxide form of Vit K being reduced.
This prevents the gamma-carboxylation of factors 2, 7, 9, 10 and proteins C & S
How is Warfarin treatment started?
Why is there an INR? (international normalised ration)
Different brands of PT have different sensitivities for detecting reduced coagulation factors, so standardisation of test is needed to achieve clinical safety for patients treated with warfarin.
What are the therapeutic ranges for warfarin?
What are the problems with warfarin?
- Warfarin has a long half life (the effect of dose change is slow)
- Many drug and food interactions exist
- may increase or decrease warfarin effect
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- may increase or decrease warfarin effect
What is used instead of warfarin alot of the time now, and acts directly as an anti-thrombin inhibitor by binding to its active site
When using fibrinolysis to treat thrombosis, what can be used?
- Streptokinase
- bacterial product
- antibodies formed - may block activity
- Tissue plasminogen activator
- Rc human product
- High cost
- Early acute MI, some acute stroke cases
