Thrombosis - formation of blood clot in vessel
 Causes ischaemia (low blood flow to (Virchows Triad)
organ)
  
Thrombotic Disorders:
1. Venous Thrombosis
 DVT - in legs
 PE - blocked supply to lungs
2. Arterial Thrombosis
 Myocardial infarction
 Atrial fibrillation
 Peripheral vascular disease
 Stroke
VTE (venous thromboembolism) - includes
DVT and PE
1. DVT - can lead to Pulmonary
Embolism (PE)
 Blood clot around valves in DEEP
VEINS (around legs/arms)
 Blood clot made of thrombus (fibrin
and erythrocyte rich)
 
2. Pulmonary embolism (PE) - part of
DVT thrombus called embolus breaks
off and travels to heart then lungs and
blocks the arteries in the lungs =
causes low blood supply to tissues
 PE always caused by DVT
 Broken off DVT = embolus
 D-Dimer - chemical released from
fibrin clots (high in PE patients)
 
Risk Factors for VTE:
 Surgery and cancer can cause high TF
= more clotting
 Immobilisation
 Genetic risk factors - Factor 5 Leiden
Mutation + Coagulation inhibitor
deficiency
 
Factor 5 Leiden mutation = mutation in factor
5 to APC cleavage = more coagulation)
Risk Factors Divided into 3 Main Categories
1. Circulatory Stasis - slow blood flow
2. Endothelial Injury (injury to
endothelium)
3. Hypercoagulable State - tendency to
form excess clots
 
Note - THROMBOPHILIA = excess abnormal
clot formation
 
Thrombosis - caused by procoagulant and
anti-fibrinolytic mechanisms
Bleeding - caused by anticoagulant +
profibrinolytic mechanisms
Note - Myocardial infarction (heart attack) =
blocked coronary arteries
 
Natural Coagulation Inhibitors in Blood:
1. Antithrombin (AT)
 Inhibits thrombin, 9a and 10a
3. Tissue factor pathway inhibitor (TFPI)
 Direct inhibitor of 7a/TF and 10a
4. Activated Protein C (aPC)
 Proteolytically cleaves 5a and 8a for
deactivation
5. Protein S (PS)
 Cofactor of aPC - helps inactivate 5a
and 8a
Deficiency in Coagulation Inhibitors:
Idiopathy - no clear triggering factor
 50% of idiopathic patients with
thrombosis have APC resistance (like
FVL)
 
Factor 5 Leiden (FVL) - mutation in F5 gene
(ARGININE 506 to GLUTAMINE 506)
 Common cause of venous thrombosis
 
Normally Activated Protein C (APC) cleaves 3
peptide bonds in F5 = INACTIVATION = low
coagulation
 mutation in FVL gene = F5 resistance
Treatment of Venous Thrombosis: (like DVT
and PE)
 Heparin (ANTITHROMBIN and ANTI
10) - Unfractionated Heparin or Low
Molecular Weight Heparin
(LMWH/Timaparin) - low molecular
weight heparin cleaves ONLY FACTOR
10
 VKA (vitamin K antagonist) - inhibits
vitamin K (vitamin K dependent
factors don’t work)
 NOACs (non-vitamin K anticoagulants)
- antithrombin
 
Arterial Thrombosis: (caused by
atherosclerosis)
 Inflammation of vessel wall
(macrophages become FOAM CELLS +
LDL fat) creates an atherosclerotic
plaque around tunica intima which
narrows artery)
 Plaque rupture causes myocardial
infarction or ischaemic stroke
 
Note - thrombus (blood clot) are platelet rich
 
Arterial Thrombosis Risk Factors:
 Smoking
 Diabetes
 Hypertension
 High cholesterol
Fibrinolysis - break down of fibrin clot
Plaque rupture causes clot to develop which
causes myocardial infarction or ischaemic
stroke
 
Plaques are made of lots of TF and Collagen
and LPA
 Big plaques rupture causes TF and
Collagen leak which activates clotting
factors which causes a thrombus
blockage (ARTERIAL THROMBOSIS) +
ischaemia
 
Collagen - activates platelets via GP6 receptor
TF expressed by FOAM CELLS - binds factor 7 -
activates coagulation
Lysophosphatidic Acid (LPA) activates
platelets via P2Y receptor
 Atherosclerosis causes narrowing of
coronary arteries
 
Carotid artery - supplies blood to brain, neck
and face
 
Effects of arterial thrombosis:
 Coronary artery thrombosis =
myocardial infarction
 Carotid artery = stroke
 
Drugs used to treat arterial thrombosis:
1. Anti-platelets
 Aspirin - inhibits COX-1 and
thromboxane production
 Anti A2B3 receptor (fibrinogen and
VWF binding)
 Anti P2Y receptor (for ADP induced
platelet aggregation)
2. Fibrinolytics - TPA (TISSUE
PLASMINOGEN ACTIVATOR) and UPA
 
 
Anti A2B3:
ABCIXIMAB
TIROFIBAN
 
Anti P2Y
CLOPIDOGREL
TICAGRELOR
PRASUGREL
PREVENTION of Stroke in atrial fibrillation:
 VKA (vitamin K antagonists)
 NOACS (either inhibit thrombin or
factor 10a) - named with either XA in
word for anti 10 or 'TRAN' at the end
for anti thrombin
TRAN - ANTI THROMBIN + Argatroban
 
Heparin - helps NOACs inhibit thrombin and
10a
  
Problem with anticoagulant drugs:
 Heparin can be impure - can cause
thrombocytopenia
 Warfarin - needs close monitoring
 Too much anticoagulant = bleeding