Theme 2: Lecture 7 - Thrombotic disorders Flashcards
DVT
Deep vein thrombrosis
Describe how DVT happens
- Due to activation of the clotting cascade in the veins when blood flow slows down
- This will cause swelling of the leg
- An embolus could break off and and travel to the lungs - life threatening
3 risk factors of Virchow’s triad
- Circulatory stasis
- Endothelial injury
- Hypercoagulable state
Thrombotic risk factors
- Post-operative, especially orthopaedic
- Hospitalisation
- Cancer
- Pregnancy
- Oral contraceptive pill
- Long-haul flights
- Obesity
- i.v. drug abuse
Presentation of DVT
- Can be no symptoms at all – clinically silent
- Unilateral calf swelling/ heat/ pain/ redness/ hardness
Differential diagnosis of DVT
- cellulitis
- Baker’s cyst
- muscular pain
Cellulitis
a common, potentially serious bacterial skin infection
Baker’s cyst
- A Baker’s cyst can form when joint-lubricating fluid fills a cushioning pouch (bursa) at the back of your knee.
- A Baker’s cyst is a fluid-filled cyst that causes a bulge and a feeling of tightness behind your knee
How is DVT diagnosed
Doppler ultrasound
What is the likelihood of of having a DVT assessed by
- D-dimer test
- Wells risk score
What do D-dimers indicate
activation of the clotting cascade
Negative predictive value
- Represents the probability that a person does not have a disease or condition, given a negative test result.
- NPV represents the proportion of individuals with negative test results who are correctly identified or diagnosed
What does a low wells score and a negative D-dimer test mean
There is a high negative predictive value for DVT, more than 99%
Initial treatment for above the knee DVT
- Therapeutic anti-coagulation using sub-cut LMW heparin (such as tinzaparin or enoxaparin)
- Dose of LMW heparin according to patient’s weight
- LMW heparin used as a bridge before patient can be treated with warfarin
- No monitoring required (but can use anti-Xa assay)
- Ensure adequate EGFR > 30ml/min
- Otherwise use iv unfractionated heparin (APTR 2.0)
Name 3 LMW heparin drugs
- Tinzaparin
- Enoxaparin
- Dalteparin
EGFR
estimated glomerular filtration rate
What is an adequate EGFR
> 30mL/min
When is LMW heparin stopped for treating DVT
once the INR > 2.0 for 2 days
How long is the patient treated with anticoagulation after their first DVT
6 months
How long is the patient treated with anticoagulation after their 2nd DVT/PE
lifelong
How often is the INR monitored on treatment with anticoagulants
every 3 weeks
What should the INR be
between 2.0-3.0 (target of 2.5)
What drug is the patient switched to after the initial treatment with LMW heparin for DVT
oral warfarin
Clinical presentation of a micro emboli
asymptomatic
Classic symptoms of PE
- pleuritic pain
- dyspnoea
- haemoptysis
haemoptysis
coughing up blood
What can a massive PE cause
- syncope
- death
What is seen on examination of a patient with PE
- tachycardia
- tachypnoea
- hypotension
Saddle embolus
- A blockage of in one of the arteries of the lungs
- An embolus that’s come from a deep vein in the leg, travelled to the lungs and impacted at the bifurcation of the pulmonary arteries
What are the investigations of a PE
- CT pulmonary angiogram
- V/Q scan
- ECG
- CXR
What is seen in a V/Q scan for PE
- ventilation/perfusion radio-isotope scan
- Underperfusion ~ V/Q mismatch
- Limitation: underlying lung disease
- rarely done
What is seen in a CXR for PE
- Usually normal
- Linear atelectasis
- Small effusions
atelectasis
collapse or closure of a lung resulting in reduced or absent gas exchange
What is seen in an ECG for PE
- Sinus tachycardia
- Atrial fibrillation
- Right heart strain (RBBB)
- Classic ECG trace SI, QIII, TIII (rare)
Alteplase
A tissue plasminogen activator
Treatment of massive PE
- A tissue plasminogen activator e.g. alteplase
- iv unfractionated heparin
tissue plasminogen activator (tPA)
- involved in the breakdown of blood clots
- catalyses conversion of plasminogen to plasmin
Treatment of standard PE
- LMW heparin injections – e.g. tinzaparin
- Warfarin (target INR 2.5) for 6 months
- Consider underlying causes
- LMW heparin is better if underlying cancer
- IVC filters (inferior vena cava filter)
- Consider a DOAC as an alternative
inferior vena cava filter
small metal device that traps large clot fragments and prevents them from traveling through the vena cava vein to the heart and lungs
Thrombophilia
clinical states in which you are prone to clot
When is a thrombophilia screen considered
in young patients with spontaneous venous thromboembolisms
Inherited causes of thrombophilia
- Factor V Leiden (5% of people)
- Deficiency of natural anticoagulants: Anti-thrombin deficiency, Protein C deficiency, Protein S deficiency
Acquired causes of thrombophilia
-Anti-phospholipid syndrome
anti-phospholipid syndrom
- Acquired cause of thrombophilia
- Auto immune disorder in which the bodies own antibodies attack your own phospholipids
What is used to test for anti-phospholipid syndrome
- Test for lupus anticoagulant using the dilute Russell viper venom time test (DRVVT)
- Anticardiolipin antibodies
Name 7 anti-thrombotic drugs/types of anti-thrombotic drugs
- Warfarin
- Heparin (unfractionated and LMW)
- direct oral thrombin (factor IIa) inhibitor
- direct oral factor Xa inhibitors
- Anti-platelet drugs
- fibrinolytic agents (thrombolytics)
What does warfarin do
- Vitamin K antagonist
- Prevents γ-carboxylation of factors II, VII, IX, X -(Required for functional maturation of these factors)
- Prolongs the extrinsic pathway (prothrombin time)
- Also inhibits natural anticoagulants Protein C and S
What is warfarin monitored by
- international normalised ratio (INR)
- Target INR usually 2.5 for DVT/PE and AF
- Target 3.5 for recurrent VTE or metal heart valves
Why can warfarin take 3 days to achieve therapeutic levels
half life of prothrombin (factor II) is 60 hours
Warfarin interactions
- Beware drug interactions due to cytochrome P450
- Beware interaction with alcohol
- Binding to albumin
- Absorption of vitamin K from GI tract
- Synthesis of vitamin K factor by liver
- Hereditary resistance
What do enzyme inhibitors of cytochrome P450 do in relation to warfarin
potentiate warfarin
What do enzyme inducers of cytochrome P450 do in relation to warfarin
inhibit warfarin
What does binge drinking do in relation to warfarin
potentiate warfarin
What does chronic alcoholism do in relation to warfarin
inhibit warfarin
Side effects of warfarin
-Teratogenic – therefore use LMW heparin in pregnancy
-Significant haemorrhage risk:
intra-cranial bleeds up to 1% per year
increased risk in elderly and with higher INR target
-Minor bleeding up to 20% per year
-Skin necrosis
-Alopecia
Teratogenic
substances that may cause birth defects via a toxic effect on an embryo or foetus
Alopecia
hair loss
What do you give to reverse the effects of warfarin in a life threatening bleed
- give activated prothrombin complex (e.g., Octaplex or Beriplex) which contains vitamin K dependent factors II, VII, IX and X
- Dose is 25-50 units per kg depending on INR level
examples of activated prothrombin complex
- Octaplex
- Beriplex
What else is given to reverse the effects of warfarin if it isn’t a life threatening bleed
- vitamin K
- fresh frozen plasma (contains all your clotting factors)
What dose of vitamin K is given to reverse the effect of warfarin
2-10mg through iv/op depending on INR level (patient can become resistant to re-loading with warfarin)
anti thrombin
small protein molecule that inactivates several enzymes of the coagulation system
What is heparin
- Mucopolysaccharide that works by potentiating anti-thrombin
- Irreversibly inactivates factor IIa (thrombin) and factor Xa
Is heparin safe in pregnancy
yes
What are the two formulations of heparin
- Unfractionated heparin
- Low molecular weight heparin
How is unfractionated heparin administered
- iv infusion
- Not often used due to inconvenience of administration
- Given i.v. with 5000U bolus and ~1000U/hour infusion
How is LMW heparin administered
- s.c injections
- very convenient
How is dose of unfractionated heparin monitored
APTT ratio (APTR) with target of 2.0 x normal
Why is unfractionated heparin safe in renal failure
unfractionated heparin is metabolised by the liver and not renally excreted
What is used to partially reverse heparin if bleeding
protamine sulfate
What is a rare complication from giving unfractionated heparin
heparin induced thrombocytopenia (HIT)
heparin induced thrombocytopenia (HIT)
- Suspect if platelet count falls on heparin
- This is paradoxically a prothrombotic condition that can cause VTE
- Diagnosis by doing a HIT screen and discontinuation of heparin
What must the patient have to be able to have LMW heparin administered
creatinine clearance of over 30mL/min as LMW is excreted by the kidneys
Benefits of DOACs
- No monitoring
- Flat dosing
- Good safety profile
What are the two classes of DOACs
- direct thrombin (IIa) inhibitor
- direct factor Xa inhibitor
When should DOACs not be used as a an alternative to warfarin
for cardiac valves
Rivaroxaban
- A DOAC
- Direct factor Xa inhibitor
- Causes irreversible anti-coagulation
Indications for using rivaroxaban
- VTE prophylaxis
- Used for treatment of DVTs and PEs
- Stroke prevention in atrial fibrillation
What is an alternate anti-Xa drug to rivaroxaban
Apixaban (less affected by renal function)
Dabigatran
- A DOAC
- Direct thrombin (IIa) inhibitor
Indications for using dabigatran
- VTE prophylaxis
- Used for treatment of DVTs and PEs
- Stroke prevention in atrial fibrillation
What can dabigatran be reversed by
Praxbind
Dosing for dabigatran
- Treatment dose is 150mg bd (bi daily)
- Prophylactic dose is 110mg bd
- Confirm creatinine clearance > 30ml/min
Dosing for rivaroxaban
Dosing is 15mg bd for 3 weeks, then 20mg od (15mg od if CrCl is 15-50ml/min)
CrCl = Creatine clearance
Name 5 anti-platelet drugs
- Aspirin
- Clopidogrel
- Dipyridamole
- Prostacyclin
- Gloycoprotein IIb/IIIa inhibitors
Aspirin
- An anti-platelet drug
- cyclo-oxygenase inhibitor
Clopidogrel
- An anti-platelet drug
- ADP receptor blocker
Dipyridamole
- An anti-platelet drug
- inhibits phosphodiesterase
Prostacyclin
- An anti-platelet drug
- Stimulates adenylate cyclase
Glycoprotein IIb/IIIa inhibitors
- An anti-platelet drug
- used in angioplasty procedures
What do fibrinolytic agents do
lyse fresh thrombi (usually arterial) by converting plasminogen to plasmin
Name 3 fibrinolytic agents
- Tissue plasminogen activator (e.g Alteplase)
- Streptokinase
- Urokinase
When are fibrinolytic agents administered
Administered systemically in:
- acute MI
- recent thrombotic stroke
- major PE
- massive iliofemoral thrombosis
