Haem: Thrombosis Aetiology and Management Flashcards
Why is thrombosis important?
- Prevalant cause of morbidity and mortality especially in hospital patients
- Significant sequelae (death is rapid)
- Preventable (thromboprophylaxis)
- May be an indicator of underlying disease (cancer)
What is an important risk factor for VTE?
Age - risk of VTE doubles every decade. There is a greater risk for PE than DVT.
What are 4 main consequences of thromboembolism?
- Death - mortality rate is 5%
- Recurrence - 20% in first 2 years and 4% pa thereafter
- Thrombophlebitic syndrome (recurrent pain, swelling and ulcers) - Severe TPS in 23% at 2 years
- Pulmonary hypertension - 4% at 2 years
What is thrombophlebitic syndrome characterized by?
Thrombophlebetic syndrome:
- Swelling
- Painful
- Eventual ulcers
What is a serious complication of thromboembolism?
Chronic thromboembolic pulmonary hypertension - extremely debilitating and often fatal disorder
What is Virchow’s triad?
There are three contributory factors to thrombosis:
Blood
Vessel wall
Blood flow
What determines the viscosity of blood?
Haematocrit - more RBCs and less plasma means more likely to thrombose
Protein/Paraprotein content - in the plasma this increases viscosity. This may be related to multiple myeloma.
What 3 factors of the blood may effect risk of thrombosis?
- Viscosity - haematocrit, protein/paraprotein
- Platelet count
- Coagulation system - triggered by tissue factor, generates thrombin, thrombin converts fibrinogen to fibrin
Draw out the extrinsic and common pathway of the coagulation cascade.
Give a list of procoagulant factors.
- V
- VIII
- XI
- IX
- X
- II
- Fibrinogen
- Platelets
Draw the coagulation cascade with the addition of regulators of coagulation.
- TFPI
- Protein C and S
- Antithrombin
These are the main regulators of coagulation
Give a list of anticoagulant factors.
- TFPI
- Protein C
- Protein S
- Thrombomodulin
- EPCR
- Antithrombin
- Fibrinolysis
Give examples of thrombophilic traits and their severity.
In order of severity:
- Protein S deficiency
- Protein C deficiency
- Antithrombin deficiency
- Factor V Leiden
Over 50-60 years, most people with protein C and S deficiency are getting thrombosis. Rate of thrombosis is about 1% per annum for these people.
What percent of thrombotic events are precipitated in people with thrombophilic traits?
50% of these thrombotic events are precipitated - partly attributed to the deficiency of an anticoagulant, but this is not the whole story. There will be other factors e.g. pregnancy, cancer, broken leg, surgery etc.
In what ways it the vessel wall normally antithrombotic?
- Expresses anticoagulant molecules
- Thrombomodulin
- Endothelial protein C receptor
- Tissue factor pathway inhibitor
- Heparans
- Does not express tissue factor
- Secretes antiplatelet factors
- Prostacyclin
- NO
What may cause the vessel wall to become prothrombotic?
Stimulus:
- Infection
- Malignancy
- Vasculitis
- Trauma
How does the vessel wall become prothrombotic?
- Anticoagulant molecules (eg TM) are down regulated
- Adhesion molecules upregulated
- TF may be expressed
- Prostacyclin production decreased
If you have a metastatic disease, what is the chance of thrombosis?
4% - this is much higher than the background rate in the population
How does stasis of blood flow promote thrombosis?
- Accumulation of activated factors
- Promotes platelet adhesion
- Promotes leukocyte adhesion and transmigration
- Hypoxia produces inflammatory effect on endothelium
What are causes of blood stasis?
- Immobility
- Surgery, Paraparesis, Travel
- Compression
- Tumour, pregnancy
- Viscosity
- Polycythaemia, Paraprotein
- Congenital
- Vascular abnormalities
Thrombotic risk factors often ______ to produce thrombosis. Thrombotic factors may have power _____ that are unpredictable.
Thrombotic risk factors often combine to produce thrombosis. Thrombotic factors may have powerful interactions that are unpredictable.
Describe the combining mechanisms that increase risk of thrombosis in:
- Pregnancy
- Malignancy
- Surgery
- Pregnancy:
- increases VIII, Fibrinogen
- decreases Protein S
- reduces flow
- Malignancy:
- increases TF expression on tumour cells
- Inflammation
- Obstructs blood flow
- Surgery:
- Trauma
- Inflammation
- Reduced flow
What are the 2 main uses of anticoagulation therapy?
- Therapeutic dose (high dose) - used on the wards for people who have had thrombosis. The whole coagulation system is very active so needs to stop.
- Prophylactic (low dose) - when anticipating entering a risky period or if somebody is a high-risk patient and entering a high risk circumstance we give a low dose as prophylaxis.
Give examples of immediately acting anticoagulant drugs.
- Heparin
- Unfractionated heparain
- Low molecular weight heparin
- Direct acting anti-Xa and anti-IIa (DOACs)
Give examples of delayed acting anticoagulant drugs.
Warfarin (Vit K antagonist)
What is the mechanism of action of heparins?
Heparins include:
- Unfractionated heparin (IV infusion)
- Low molecular weight heparin (sub cutaneous)
- Pentasaccharide (sub cutaneous)
They all act by potentiating antithrombin.
They provide immediate effect (e.g. for treatment of thrombosis)
What are the disadvantages of using heparin?
- Long term disadvatnage - injections, risk of osteoporosis and thrombocytopaenia
- Variable renal dependence - depends on pt renal function
LMWH has reliable pharmacokinetics so does not usually require constant monitoring. In what circumstances is monitoring required?
Monitoring is required in patients with renal impairment (CrCl<50) or at extreme weights.
Can use an anti-Xa assay to monitor.
Why is it necessary to monitor unfractionated heparin?
Unfractionated heparin has:
- Variable kinetics
- Variable dose-response
- Always monitor therapeutic levels with APTT and anti-Xa
When is unfractionated heparin used?
Unfractionated heparin is used in ICU but needs to monitored careful. It is given by infusion and it can be turned “off” and “on”.
It is monitored by APTT.
Unfractionated heparin is used in patients with renal failure.
Give examples of anti-Xa DOACs.
Rivaroxaban, Apixaban, Edoxaban
Give examples of anti-IIa DOACs.
Dabigatran
What properties do DOACs have?
- Oral administration
- Immediate acting - peak in approx. 3-4 hours (cf LMWH)
- Also useful in long term
- Short half-life - reasonably quick ON and OFF effect
- Don’t need monitoring
How is Warfarin given and what is its mechanism of action?
- Warfarin is given orally
- Indirect effect by preventing recycling of Vit K, blocks vitamin K epoxide reductase
- Therefore onset of action is delayer
- Levels of procoagulant factors II, VII, IX and X fall
- Levels of anticoagulant protein C and protein S also fall
What is the antidote to Warfarin?
Vitamin K
This takes time
Which factors are reduced with Warfarin and how long does it take for this to have an effect?
Factors 2, 7, 9 and 10 are reduced by Warfarin. This takes 5-7 days before any significant effect occurs.
Warfarin is no good for treating DVTs immediately.
How is warfarin monitored?
Measure the effect of warfarin using the Internatinal Normalised Ratio (INR).
INR is derived from prothrombin time.
Why is it essential to monitor Warfarin use?
The dose needed to achieve an anticoagulant effect is variable so dose must be monitored.
There is great variation in effect due to numerous interactions:
- Dietary Vit K
- Variable absorption
- Interactions with other drugs
- Protein binding, competition/induction of cytochromes
- Teratogenic
What dietary foods are rich in vitamin K?
Broccoli and Kale
What drugs are known to interact with Warfarin?
Warfarin interacts with many drugs including Rifampycin and Amiodarone.
What is a major contraindiction against warfarin use?
Pregnancy. Warfarin is teratogenic.
Does increasing INR mean a decrease or increase in thrombosis risk?
Higher INR means decreased risk of thrombosis.
What is the aim for INR levels in patients with prosthetic valves?
We aim for an INR of 4.0.
Safe region is from 2.0-6.0
Who is at an increased risk of thrombosis?
- Medical in patients
- Infection/inflammation, immobility (inc stroke), age
- Patients with cancer
- Procoag molecules, inflammation, flow obstruction
- Surgical patients
- Immobility, trauma, inflammation
- Previous VTE, family history, genetic traits
- Obese
- Elderly
What may be given as thromboprophylaxis?
- LMWH
- E.g Tinzaparin 4500u/ Clexan 40mg
- Not monitored
- Rivaroxaban
- TED stockings (for surgery or if heparin C/I)
- Intermittent compression (increases flow)
All admissions to hospital must be assessed for ________ risk and unless _________ exists, receive _________ prophylaxis.
All admisions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis.
What patient factors increase risk of VTE?
- Age >60yrs
- Previous VTE
- Active cancer
- Acute or chronic lung disease
- Chronic heart failure
- Lower limb paralysis (excluding acute CVA)
- Acute infection
- BMI>30
What surgical procedures increase risk of VTE?
- Hip or knee replacement
- Hip fracture
- Other major orthopadic surgery
- Surgery >30 mins
- Plaster cast immobilisation of lower limb
What scoring system may be used to calculate DVT risk?
WELL’S Score
What patient factors increase risk of bleeding?
- Bleeding diathesis (eg haemophilia, VWD)
- Platelets <100
- Acute CVA in previous month (H’gge or thromb)
- BP>200 syst or 120 diast
- Severe liver disease
- Severe renal disease
- Active bleeding
- Anticoag or anti-platelet therapy
What surgical procedures increase risk of bleeding?
- Neuro, spinal or eye surgery
- Other with high bleeding risk
- Lumbar puncture / spinal / epidural in previous 4 hours
What scoring system can be used to calculate risk of bleeding?
HAS-BLED score
What is the treatment for DVT/PE?
- Immediate anticoagulation is essential
- Start LMWH e.g. Tinzaparin 175u/Kg and DOAC
- Stop LMWH when INR>2 for 2 days
- Treat the patient with anticoagulation therapy for 3-6 months period
Patients with cancer: continue LMWH not warfarin
When are clot dissolving treatments used?
- Only used for life threatening PE or limb threatening DVT
- Risk of haemorrhage (ICH) ~4%
- Reduce subsequent post-phlebitic syndrome
- Indications broadening slowly
What must be taken into account when assesing whether to start long-term anticoagulation?
Need to assess:
- Risk of recurrence
- Morbidity and mortality of recurrence
- Risk of therapy (bleeding)
- Morbidity and mortality of bleeding
- Variation of risks with different therapies
How do we assess risk of thrombosis recurrence?
The circumstances of the thrombosis is the key factor - need to understand how much of the thrombosis is due to external factors and how much due to intrinsic.
Surgery recurrence rate is very small - there is only a short term risk.
Non-surgical risk (e.g. COCP, flights) - slightly higher recurrence rate
Idiopathic thrombosis - no external factor. May be due to underlying genetic problem. Have the highest recurrence rate (12% in the following year)
In which group of people is long term anticoagulation given to indefinitely?
Those who have had idiopathic thrombosis due to high rate of recurrence.
How does gender affect risk of VTE recurrence?
Men are more prone to get recurrence - 3.6x more likely.
If male and idiopathic thrombosis, definitely use long-term anticoagulation.
When should long term anticoagulation be considering?
- Very low after surgical precipitant
- No need for long term anticoagulation
- High recurrence after idiopathic VTE (20% in 2yrs)
- Consider long term anticoagulation
- Minor precipitants (COCP, flights, trauma)
- Usually 3 months adequate
- Longer duration may be dictate by presence of other thrombotic and haemorrhagic risk factors
