DVT and pulmonary embolism Flashcards
What type of DVT (deep vein thrombosis) can be a big risk?
above knee DVT – associated with embolic events
What type of risk does DVT have?
Multifactorial risk
How does DVT form?
• Thrombus in deep vein around valves
• Multiple triggers – finely balanced system is destabilised
•
What is a pulmonary embolus?
fragmentation of proximal clot which travels in venous system until it lodges in the pulmonary circulation
Where are the consequences of DVT?
Consequences locally in source limb and/or in heart or lungs after embolization
What is Virchow’s triad and what does it include?
contributing factors to thrombosis:
- Endothelial injury
- Stasis
• Blood components o Platelets o Coagulation factors o Coagulation inhibitors o Fibrinolytic factors
What happens as we get older?
We get more thrombotic as we get older
How does a haemostatic plug form?
- Release of tissue factor from vessel injury
- Coagulation cascade activated
- Vessel injury also platelet release reaction and vasoconstriction
- They all combine to form a stable haemostatic plug
What is present at the site of the clot?
- Tissue factor
- activating factors
- conversion of prothrombin to thrombin
- Activated platelets and platelet complexes
- Fibrinogen converted to fibrin
What forms the clot?
Cascade forms a clot
Cascade is self-perpetuating until something stops it
What are the phases of the cascade?
3 phases of cascade:
- initiation
- amplification
- propagation (this produces clot)
if these phases are interrupted the process is terminated
Which pathways can activate the cascade?
extrinsic and intrinsic pathways
What 2 things are part of the extrinsic pathway?
Tissue factor and vessel damage are part of the extrinsic pathway – more important than intrinsic pathway
What is crucial in the cascade regardless of the pathway?
conversion of factor 10 to 10a
What does factor 10a do and how does this lead to the production of a thrombus?
- It acts on prothrombin to thrombin, which activates conversion of fibrinogen to fibrin
- Activation of factor 13 and cross linked fibrin produces thrombus
What helps control the clotting cascade?
There’s inhibitors to balance:
• Proteins C and S – combine to make activated protein C
o Act on factor Va and VIIIa
• Anti-thrombin acts on X and thrombin
What can change the homeostatic point for the clotting cascade?
Defects in protein and C or S change the homeostatic point for clotting cascade
Why does the haemostatic plug form? and how does it form?
Haemostatic plug formation: Response to injury
- Vessel constriction
- Formation of unstable platelet plug
• platelet adhesion
• platelet aggregation - Fibrin stabilisation of the plug with fibrin
• blood coagulation - Dissolution of clot and vessel repair
• Intrinsic fibrinolysis
What happens in fibrinolysis?
- Tissue plasminogen activator converts plasminogen into plasmin
- It breaks down fibrin cross linking strands into D-dimer
- Raised D-dimer levels suggest tissue inflammation or active breakdown of fibrin clot
Where are clotting factors, fibrinolytic factors and inhibitors synthesised?
- liver
- endothelium
- megakaryocytes (platelets)
What are some measurements used in DVT/PE/clotting cascade?
- Prothrombin time – PT = PTR
- Partial thromboplastin time – APTT =APTTR
- Thrombin time - TT
What are the risk factors for venous thrombosis?
Stasis
• Prolonged immobility eg surgery, travel
• Stroke
• Cardiac failure
Coagulation abnormality • Surgery or major trauma • Pregnancy and puerperium • Oestrogen medication • Malignancy
Others • Age • Past history or family history of VTE • Obesity • COVID-19
What are the 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
How is DVT diagnosed?
- Risk assessment
- Evidence based pre-test probability score (well’s score) – combines clinical factors in an evidence based way (determines role for diagnostic imaging vs use of blood test for exclusion)
- D dimer for exclusion
- Diagnostic tests
- Compression ultrasonography
- Venography
What are the clinical features of pulmonary embolism?
Depends on where it lodges
• Peripheral: problems with ventilation perfusion mismatch
• Centrally in bigger vessels: pressure effects
What are the symptoms of PE?
- Dyspnoea
- Pleuritic chest pain
- Cough and haemoptysis
- Dizziness
- Syncope
- Importantly the patient may be very unwell or very well – some patients get very few symptoms
What are the signs of PE?
- Tachypnoea, tachycardia
- Hypoxia
- Pyrexia
- Elevated jugular venous pressure
- Hypotension – due to proximal pulmonary artery occlusion
- ECG changes
What is the physiology of symptoms and signs of PE?
- Symptoms and signs determined by thrombus size and burden
- Multiple small peripheral thrombi produce a different clinical picture to large proximal thrombus
- Pulmonary infarction is not common – remember the bronchial circulation
How is PE diagnosed?
- Risk assessment and diagnostic algorithm
- D – dimer for exclusion in low risk cases only
- Mortality stratification - PESI score
- Assessment of compromise - Pa02 (gas exchange) + D dimer + ECG + increase troponin and BNP indicate damage to myocardium and strain on heart
- Consider echocardiogram
What diagnostic tests are used if other tests don’t give a certain diagnosis?
- CT pulmonary arteries – CTPA
* Ventilation Perfusion Scan – used for pregnant patients to avoid radiation to pregnant breasts
What are the long term consequences of venous thromboembolism?
- 10% of all hospital deaths
- 30% recurrence at 10 years
- 30% post phlebitic syndrome at 10 years
- Chronic thromboembolic pulmonary hypertension (CTEPH)
What are the treatments of VTE?
- Anticoagulants
- Thrombolysis
- Surgery
What are the main targets of the VTE treatment?
• The thrombus
• Two approaches:
o Lyse the thrombus
o Prevent further thrombus formation
What is the problem with lysis?
Lysis has the problem that if given systemically it lyses all thrombus everywhere
What do most treatments aim for?
Most treatment aims to:
- prevent thrombus propagation and formation of new thrombus
- while allowing the body to concentrate lysis in the place where it is required
What are the usual risk of VTE treatments?
Risks are short term impact of thrombus burden and damage to vessels while thrombus remains
Treatment of acute cardiovascularly stable VTE?
– Anticoagulate
o Immediate anticoagulant effect
o Heparin then warfarin/DOAC or immediate DOAC- Rivaroxaban or apixaban
Treatment when there is a circulatory collapse due to PE or severe DVT?
– Thrombolysis
o Alteplase (tissue plasminogen activator)
o (Streptokinase)
o Followed by heparin and warfarin or other – prevent recurrence
What investigations are done pre-treatment?
• Clotting screen
o Prothrombin time (INR)
o Partial thromboplastin time
o Thrombin time
• Full blood count – make sure theyre not anaemic
• Urea and electrolytes
o usually part of routine screen – to know creatinine clearance
• Liver function tests
o If clinical suspicion of liver disease – can affect drug excretion
What does thrombin time tell?
tells time from fibrinogen to fibrin formation – tells how heparin works
What does prothrombin time tell?
tells about extrinsic pathway, how long it takes to clot after you add tissue factor. important if:
o patients have liver disease affects clotting factor synthesis
o if patients is on warfarin
o if patient has vitamin k deficiency
What does partial thromboplastin time tell?
tells about intrinsic pathway, tells if
o Patient has clotting factor deficient
o Patient has sepsis
What is heparin (UFH)?
- It’s a Glycosaminoglycan
- Irreversible in binding
- Immediate action
- Parenteral administration, iv or sc
- Renal excretion
How is UFH monitored?
Activated Partial Thromboplastin Time Ratio – APTTR
What prolongs the baseline levels of UFH?
o baseline level prolonged by
- antiphospholipid antibodies
- combined Rx with warfarin or thrombolytics
- congenital factor deficiencies
What shortens the baseline levels of UFH?
o baseline level shortened by
- high Vlll
What is a challenge with UFH?
actually difficult to achieve reliable anticoagulation
How does UFH bind?
Binds irreversibly to thrombin and other molecules
Different people have different balance between components – causes different effects in people
Where is unfractionated heparin (UFH) synthesised and what does it do?
- biosynthesis: mast cells
- accelerates inhibition of thrombin (IIa) and Xa
- bioavailability 30%
- t ½ 1-2 hours
How is low molecular weight heparin (LMWH) made and what does it do?
- fractionation from UFH
- accelerates inhibition of Xa from converting to thrombin (IIa)
- bioavailability 90%
- t ½ 4-12 hours
How is LMWH cleared?
Renally cleared
When is anti-Xa monitoring needed?
• Anti Xa monitoring performed under certain circumstances
o Pregnancy
o Renal failure
o Obesity
What are the side effects of heparin?
• Bleeding
o LMWH: less major bleeding (more even control)
o stop heparin if there’s bleeding when UFH is given
o If LMWH causes bleeding give protamine sulphate – LMWH is harder to reverse
• Heparin induced thrombocytopenia (HIT)
o minor platelet drop at 5 days
- transient
o 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
What is the mechanism of action of Warfarin?
- Acts on a number of different places
- Vitamin k dependant clotting factor – antagonises vitamin k
- Causing synthesis of Non Functional Coagulant and Anticoagulant Factors
Sites of actions for VKA?
- Because it acts on both anti-coagulant and coagulant factors – doesn’t produce anti-coagulation immediately
- Pro-coagulant state happens first the anti-coagulant
Side effects of Warfarin?
• skin necrosis - give heparin at first with warfarin for risk of VTE
How is warfarin eliminated?
- Rapidly absorbed t½ 36 - 42 hours
* Eliminated by liver
What can affect intraindividual dose variation of Warfarin?
• Intraindividual dose variation o genetic factors o compliance / comprehension o diet o co-morbid conditions eg right heart failure o numerous drug interactions
What genes can affect the intraindividual dose variation of Warfarin?
- CYP2C9 – ↑ sensitivity
- VKORC1 – principal genetic modulator
How is Warfarin administered?
- Tablets
* Dosing -Loading algorithms and maintenance dose/they track their doses
Why is tracking doses of Warfarin important?
Because Interruptions are necessary for surgical procedures
What are the 2 ways of testing INR?
- Venous sample
- Near patient testing (NPT) finger prick
Pros/cons of venous sample
- labour intensive
- accurate
- cheap
Pros/cons of near patient testing
- capillary whole blood
- quick
- patients prefer
- immediate advice
- 0.5 variation in INR
- Expensive
What can other drugs do/how they interact with warfarin?
Drugs can:
• impair absorption of vitamin K
o increase anticoagulant effect
• compete for plasma protein binding sites
o increase anticoagulant effect
• be hepatotoxic
o increase anticoagulant effect
• induce hepatic enzymes
o reduce anticoagulant effect
• have antiplatelet activity
o cause increased bleeding
What are the annual risks of bleeding due to warfarin?
- Fatal 0.1 – 1% pa
- Major/life threatening 0.5 – 6.5 % pa ie
- Minor 6.2 – 21.8% pa eg all other bleeds
Why warfarin reversal may be needed and how is it done?
• When there’s High INR no bleeding
• Emergency reversal with: o 5mg iv Vit K o PCC (prothrombin complex concentrate) (octaplex/beriplex): replaces impaired clotting factors Factor IX Factor II Factor X Factor VII
How can warfarin affect pregnancy/the foetus?
crosses placenta
- Affects cranial development
- May cause brain bleeds in foetus
- Can get problem with bone development
- coumarin embryopathy
• increased fetal wastage
o intracerebral haemorrhage
o ante partum haemorrhage
What are the issues with warfarin?
• Narrow therapeutic window
o Frequent monitoring needed (not always available)
- Risk of bleeding (especially intracranial haemorrhage)
- Many contraindications and food and drug interactions
- Lifestyle restrictions
- Poor compliance and persistence
- Consequence: many patients are not sufficiently anticoagulated
Advantages of direct oral coagulants?
• Oral anticoagulant
• Rapid onset/offset of action
o No need for bridging
• Short half life
o Easy to control anticoagulant effect
- Little or no food-drug interactions
- Limited drug-drug interactions
•Predictable anticoagulant effect
o No need routine monitoring
What are some new anti-coagulants?
• Indirect Xa inhibitors - enhance antithrombin
o Fondaparinux
o Idraparinux
• Direct Xa inhibitors (ORAL)
o Rivaroxaban
o Apixaban
• Direct thrombin inhibitors (ORAL)
o Ximelagatran
o Dabigatran
What is rivaroxaban?
- onset?
- monitoring?
- how is it excreted?
- drug/food interactions?
- side effects?
- when is it used?
- Direct inhibitor of Xa
- Oral agent ,once daily dosing
- Rapid onset of action and half life 4-9 hours
- Monitoring not usually necessary
- Renal excretion
- Few food or drug interactions
- GI side effects
• in VTE prevention Post hip replacement
o superior to LMWH
• In VTE treatment and secondary prevention of DVT
o non inferior to LMWH and warfarin
o Now first line in many hospitals
What study was done on rivaroxaban and what did it show?
• SPAF - Rocket AF vs warfarin in 16000 patients
o non inferior
o major bleeding rate similar but less IC bleeding
What is apixaban?
- onset?
- monitoring?
- how is it excreted?
- drug/food interactions?
- side effects?
- Direct inhibitor of Xa
- Oral agent
- Rapid onset of action
- Half life 9-14hours
- Monitoring not usually necessary
- Biliary and renal excretion
- Few food or drug interactions
- GI side effects
What is dabigatran extexile?
- onset?
- monitoring?
- how is it excreted?
- drug/food interactions?
- side effects?
- cost?
- Direct thrombin inhibitor
- Oral, fixed doses
- Monitoring not usually necessary
- Rapid onset and offset of action
- Half life 12-17 hours
- Minimal food and drug interactions
- Renal excretion
- Reasonable cost
How long are anticoagulants given for VTE?
o Variable
o Minimum 6 weeks
o 3-6 months for most indications – in unprovoked thrombosis
o For period of risk
Warfarin can be stopped abruptly
What can cause secondary VTE?
- Risk factors related to initial event
- Idiopathic
- 20 to 40% percent of those with an unprovoked venous thromboembolism (VTE) experience a recurrence within five years of the initial event
- This is different in cancer – they’re prothrombotic but don’t respond well to some of the medication
What is the relation between COVID-19 and VTE
- Significant numbers of thrombotic events in COVID-19 patients who are unwell
- Very high D-dimers in many patients
- Patients appear highly prothrombotic
- Treatment is the same
