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Topics covered:
DVT and PE - Venous Thromboembolism
Mechanisms
Revision of haemostasis and thrombosis
Causes and risk factors
Clinical features and risk assessment
Pharmacological treatment
Pharmacological prevention
Pharmacology covered:
Anticoagulant drugs
Heparin
Mechanism of action
Monitoring
Side effects and reversal
Warfarin
Mechanism of action
Monitoring
Side effects and reversal
New anticoagulants
Direct thrombin inhibitors
Direct factor X inhibitors
Venous Thromboembolism
Deep Vein Thrombosis and Pulmonary Embolism
1:1000 annual incidence
Importance is above knee DVT
Larger amount of vessel damaged an more likely to spread to lungs for PE
8:100
Inherited thrombophilia
Multifactorial risk
Common for clots in veins due to turbulent flow around valves

Process
Thrombus in deep vein around valves (stasis and turbulent flow)
Multiple triggers - finely balanced system is destabilised
50% of above knee DVTs will embolise
Pulmonary embolus
Fragmentation of proximal clot which travels in venous system until it lodges in the
pulmonary circulation
Consequences locally in source limb and/or in heart or lungs after embolisation (V/F
imbalance)
Virchows triad
Endothelial injury (can be due to surgery)
Stasis
New knee/hip --> sitting around
Blood components
Platelets (less important)
Coagulation factors
Coagulation inhibitors
Fibrinolytic factors

Thrombosis is multi-factorial genetic and acquired risk factors
Cumulative risk determines if you get DVT or not

Designed to reduce blood loss

Cell based model of coagulation

TF = Tissue Factor
Fibrin holds platelets in place

Haemostatic plug formation
Amplification - once it's on it's on

Learn:

PI (Platelet membrane phospholipid)

Fibrinolysis

D-Dimer - Marker for fibrinolysis (and therefore marker for thrombus)
When you have a clot - the body dissolves it
Anti DVT medicine just stops the clot getting bigger

Natural coagulation inhibitors
Antithrombin (III)*
Protein C pathway*
(Tissue factor pathway inhibitor)

*Active inhibitors of thrombus formation

Venous Thrombosis - risk factors
Stasis
Prolonged immobility
e
...
surgery, travel
Stroke
Cardiac failure
Pelvic obstruction - Mass (cancer or baby)
Dehydration
Hyperviscosity
Polycythaemia - (increased RBC count)
Coagulation abnormality
Surgery or major trauma
Pregnancy and puerperium
Oestrogen medication (mimics pregnancy state)
Malignancy
Antiphospholipid antibodies
Hereditary or acquired thrombophilia
Thrombocytosis
Heparin induced thrombocytopenia
Others
Age
Past history or family history of VTE
Obesity
Sepsis
Nephrotic syndrome - (leak proteins out of kidneys [clotting factors])
Paroxysmal nocturnal haemoglobinuria
Behçet's disease
Clinical features of DVT
Pain, tenderness of veins
Limb swelling
Superficial venous distension
Increased skin temperature
Skin discoloration
All reflect obstruction to the venous drainage
There are multiple differential diagnoses for these presenting features
E
...
Cellulitis

DVT diagnosis
Risk assessment
Evidence based pre test probability score
D-dimer for exclusion
If its low = low fibrinolysis = low risk of DVT
Diagnostic tests
Compression Ultrasonography
I
...

Heparin then warfarin
Acute VTE
Immediate anticoagulant effect
Thrombolysis
Circulatory collapse due to PE
Alteplase (tissue plasminogen activator)
Streptokinase
Followed by heparin and warfarin
NO MORTALITY BENEFIT TO THROMBOLYSIS UNLESS JUST ABOUT TO ARREST
Investigations pre Rx
Clotting screen
Prothrombin time (INR)
Partial thromboplastin time
Thrombin time
Full blood count
Urea and electrolytes
If for LMWH for >4 days
Liver function tests
If clinical suspicion of liver disease

Heparin
Glycosaminoglycan from porcine mucosa
Irreversible
Immediate action
Parental administration, IV or subcutaneous
Renal excretion

Unfractionated Heparin (UFH)
Biosynthesis: Mast cells
MW: 5000-40,000 Da
Bioavailability: 30%
Half life: 1-2 hours
Accelerates inhibition of thrombin (II) and Xa
Low Molecular Weight Heparin (LMWH)
Fractionation from UFH
MW 4000-6500 Da
Bioavailability: 90%
Half life: 4-12 hrs
Accelerates inhibition of Xa > Thrombin (IIa)
If you are:
really paired
at the extremes of body weight
Pregnant
you may have to go back to UFH
LMWH peaks at 4 hrs post injection and troughs at 18 hrs post injection

Heparin side effects
Bleeding
LMWH vs UFH less major bleeding
Stop heparin
Give protamine sulphate
Heparin induced thrombocytopenia (HIT)
minor platelet drop at 5 days
transient
HIT with thrombosis syndrome (HITTS)
Thrombocytopenia -IgG antibody to heparin + platelet factor 4 complexes
Thrombosis - venous and arterial and gangrene
Timing - 4-5 days after starting heparin
Other cause for thrombocytopenia not found
Warfarin
Decaying sweet clover
1930s dicumarol isolated
1950 and 60s used to treat thromboembolic disease

Warfarin:
Affects many coagulation factors
Unpredictable effect of dose

Warfarin Side effects
Skin necrosis
Give Heparin first for Rx of VTE
Can make people prothrombotic!
Warfarin
Rapidly absorbed
Half life: 36-42 hrs
97% albumin bound in plasma
Pharmacological effect due to unbound fraction
Eliminated by liver (good for patients with renal failure)
Inter individual dose variation
Genetic factors
CYP2C9 - Increased sensitivity
VKORC1 - principle genetic modulator
Compliance/comprehension
Diet
Co-morbid conditions e
...
RH failure
Numerous drug interactions
Warfarin dosing
Tablets
Dosing - Loading algorithms and maintenance dose
Interruption necessary for surgical procedures
International Normalised Ratio = INR (prothrombin time ratio)
Prothrombin time ratio
International sensitivity index (ISI)
Different target range depending on context

INR testing
Venous sample
Labour intensive
Accurate
Cheap
Near patient testing (NPT) finger prick
Capillary whole blood
Quick
Patients prefer
Immediate advice
Expensive
Risk of bleeding
Fatal - 0
...
5 - 6
...
2 - 21
...
5 -2 hrs
Half life 12-17 hours
Minimal food and drug interactions
Renal excretion
No agent available for reversal - (Irreversible!)
Reasonable cost

The Future
VTE risk assessment as part of ‘health check’ of hospitals
Oral anticoagulants that do not need monitoring
Targeted anticoagulants for different indications
Alternative means of reversal
Recombinant clotting factors?



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