Lecture 30 - Thrombotic disorders Flashcards
Thrombosis
Thrombosis involves the formation of a blood clot inside a vessel, blocking the circulation.
can causes ischaemia - tissue death
difference between arterial and venous thrombosis
has very different aetiology
structure of vein
large diameter thin wall thin tunica media low pressure valves
artery structure
small diameter thick wall thick tunica media high pressure no valaves
main venous thrombosis disorders
Deep vein thrombosis (DVT; arm/leg) Pulmonary embolism (PE; lungs)
Arterial thrombosis
Myocardial infarction (MI; heart)
Atrial fibrillation (AF; heart)
Peripheral vascular disease (PVD; leg)
Stroke (brain)
Deep vein thrombosis
occurs under low blood flow
opp to arterial - high blood flow
usually around valves in deep veins - may lead to PE
Less complex phenotype that that of arterial thrombosis
25,000 deaths per annum
What is a thrombus made of
fibrin
erthyrocyte
Pulmonary Embolism (PE)
a small part of deep vein thrombus breaks off
- embolus travels via veins to RA-RV and then to RV of lung
- embolus blocks an artery in the lung leading to lung tissue infarction
Risk factors for venous thrombosis
immobilization surgery cancer Pregnancy Oral contraceptives Genetic risk factors: Deficiencies in coagulation inhibitors and Factor V Leiden mutation all causes stasis
What is virchow’s triad
three broad categories of factors that are thought to contribute to thrombosis.
- endothelial injury
- circulatory stasis (haemodynamic changes)
- hypercoagulable state
Natural inhibitors of coagulation
Antithrombin - direct inhibits thrombin - F10a and F9a
Tissue factor Pathway inhibitor (TFPI) - Direct inhibitor of F7A/TF and F10a
Activated protein C (aPC)
-proteolytically inactivates FVa and F8a
-Protein S (PS)
-Cofactor for aPC in the inactivation of F5a/F8a
What is Factor V Leiden - Inherited activated protein C resistance
Point mutation in the Factor V gene which increases the risk of deep venous thrombosis
Prevalence in Western Populations
What occurs in Factor V leiden
aPC cleaves 3 peptide bonds in FVa to inactivate it
Factor V Leiden is resistant to APC cleavage, but coagulation factor activity fully retained
What is the most common cause of idiopathic thrombosis
Inherited Activated Protein C Resistance
“Factor V Leiden”
What is arterial thrombosis
leading cause of death atherosclerosis: inflammation of vessle with infiltration of macrophages and fat deposits triggered by rupture of plaque event in MI and ischaemic stroke thrombus - platelet -rich
What happens when a atherosclerotic plaque develops
collagen type 1 and 3 activate platelets via GP6 receptor Lysophosphatidic acid (LPA) activate platelets via P2Y receptor Tissue factor (expressed by foam cells) binds F7 and activates coagulation
Arterial thrombosis in coronary artery can lead to
MI
Arterial thrombosis in Carotid artery
can lead to stroke
Drugs used for athero-thrombosis
Statins
Antiplatelets
-aspirin
-anti alpha 2 beta 3 receptor (for fibrin/ogen and vWF)
eg. Abciximab and tirofiban
-Anti P2Y (receptor for ADP induced platelet aggregation
-clopidogrel, ticagrelor, prasugrel
-fibrinolytics - tPA/uPA derivatives, now only used in stroke
Long term anti-coagulants
warfarin/coumarins
Direct thrombin inhibitors
Dabigatran, Melagatran, Argatroban
Direct Anti-Xa
Rivaroxaban, Apixaban
What anti-coagulant is used during angioplastyand other surgical procedures and why
heparin
helps AT to inhibit thrombin and 10a
to eliminate blocked vessel
Drugs used in the treatment of venous thrombosis
immediate onset:
- unfractionated heparin (intravenous to inhibit thrombin and 10a)
slow onset
- warfarin and coumarins
direct thrombin inhibitors (dabigatran) - promising in clinical trials
Problems with heparin
Heparin (obtained from porcine intestine or bovine lung) may contain impurities
(Oversulfated chondroitin sulfate story in 2008 – anaphylactic shock due to bradykinin, C3a and C5a generation)
