Haematology 5- Thrombosis: Aetiology and Management Flashcards
Consequences of Thromboembolism
- Recurrence
- Thrombophlebitic syndrome (recurrent pain, swelling and ulcers
- Pulmonary hypertension
- THREE contributory factors to thrombosis
- Blood composition
- (viscosity)
- Haematocrit (high)
- Protein/ paraprotein (high level- e.g. myeloma and paraprotein)
- Platelet count
- Coagulation – net excess of procoagulant activity
- (viscosity)
- Vessel wall
- Blood flow
procoagulant and antiocgulant factors
- Coagulation factors push to produce thrombin and eventually fibrin
SBA 1: The risk of thrombosis is increased by:
- Reduced prothrombin
- Thrombocytopenia
- Reduced Protein C
- Elevated anti-thrombin
- Increased fibrinolysis
- Reduced prothrombin
- Thrombocytopenia
- Reduced Protein C
- Elevated anti-thrombin
- Increased fibrinolysis
The Vessel Wall is normally Antithrombotic- how?
expresses anticoagulant molecules
- Thrombomodulin – help activate protein C
- Endothelial Protein C receptor – help activate protein C
- Tissue factor pathway inhibitor
- Heparans- help antithrombin work
- It does NOT express tissue factor
- It secretes antiplatelet factors:
- Prostacyclin (PGI2)
- NO
what makes Vessel Wall Prothrombotic
-
Stimulus:
- Infection
- Malignancy
- Vasculitis
- Trauma
- Hypoxia
-
Effects:
- Anticoagulant molecules (e.g. thrombomodulin) are downregulated
- Adhesion molecules upregulated
- TF may be expressed
- Prostacyclin production reduced
This becomes procoagulant which is how the vessel wall comes into play in thrombosis
Inflammation and Thrombosis: Malignancy
causes inflammation, leading to expression of tissue factor
+ can also cause obstruction
Blood Flow: Stasis promotes Thrombosis
-
Mechanism:
- There is an accumulation of activated factors
- This promotes platelet adhesion
- This also promotes leukocyte adhesion and transmigration
- Hypoxia produces inflammatory effect on endothelium
-
Causes of stasis:
- Immobility- surgery, paraparesis, travel
- Compression- tumour, pregnancy
- Viscosity- polycythaemia, paraprotein
- Congenital- vascular abnormalities
SBA 2: Which factor confers the highest risk of thrombosis?
- Factor V Leiden
- Antithrombin deficiency
- FHx of thrombosis
- Reduced Factor VIII level
- 3 hour plane flight
- Factor V Leiden
- Antithrombin deficiency
- FHx of thrombosis
- Reduced Factor VIII level
- 3 hour plane flight
Thrombotic risk factors can combine to cause a massively increased risk of thrombosis
Heparin - is it delayed use or immediate use?
disadvantages
MOA
example
Heparin– increase anticoagulant activity by potentiating anti-thrombin
LMWH (SC) + unfractionated heparin - IV
Long term disadvantages
- SC injections
- Risk of osteoporosis
- Variable renal dependence
- Direct Acting Anti-Xa and Anti-IIa (IIa- thrombin) –
- is it delayed use or immediate use?
disadvantages
MOA
example
immediate use - peak in 2-4 hours
Inhibit the activation of coagulation factors
Take orally not SC like LMWH
unfractionated heparin
warfarin
- is it delayed use or immediate use?
disadvantages
MOA
example
- DELAYED- takes 2-3 days
- Warfarin – reduce procoagulant activity
- Vitamin K epoxide reductase inhibitor >>> inhibits coagulation factor proteins 2, 7, 9, 10
- Also causes a reduction in Protein C and S
how is warfarin prophylactic + theraputic
- HIGH dose= therapeutic
- LOW dose= prophylactic
SBA 3: Which agent has a delayed anticoagulant effect?
- Vitamin K
- Unfractionated heparin
- Warfarin
- LMWH
- Aspirin
- Vitamin K
- Unfractionated heparin
- Warfarin
- LMWH
- Aspirin
Monitoring Heparin Therapy
- LMWH- Reliable pharmacokinetics so not usually required to monitor
- Unfractionated heparin
- Always monitors therapeutic levels with APTT (activated partial thromboplastin time) or anti-Xa
examples of direct acting anticoagulants + do they require monitoring
- Anti-Xa: Direct factor Xa inhibitor
- Rivaroxaban, apixaban, edoxaban
- Anti-IIa: Direct thrombin inhibitor
- Dabigatran
- No monitoring
Delayed Anticoagulation- Long Term
warfarin- mode of adminstration
MOA + how can it be reversed
- inhibits the synthesis of Vitamin K-dependent proteins (factors 2, 7, 9 and 10) >>> so delayed onset of action
- also reduces amount of protein C and S
reversed with:
- vitamin K - takes 12 hours
- giving factors 2, 7, 9, 10- immediate response
How does warfarin achieve an anticoagulant effect?
- Reduce the production of Protein C and Protein S
- Blocks phospholipid synthesis
- Reduces plasma concentration of procoagulant factors
- Acts as a cofactor for antithrombin
- Inhibits Factors II, VII, IX, X
- Reduce the production of Protein C and Protein S
- Blocks phospholipid synthesis
- Reduces plasma concentration of procoagulant factors
- Acts as a cofactor for antithrombin
- Inhibits Factors II, VII, IX, X
Monitoring Warfarin
- Measure of effect is the INR (International Normalised Ratio)-
- Derived from prothrombin time
can warfarin + heparin + DOAC be given in pregnancy
- Teratogenic
Summary of Different Anticoagulants used
Patients at Increased risk of Thrombosis
- Medical inpatients
- Infection/ inflammation
- immobility (including stroke)
- age
- Patients with cancer
- Procoagulant molecules, inflammation, flow obstruction
- Surgical inpatients
- Immobility, trauma, inflammation
- Previous VTE, FHx, genetic traits
- Obese
- Elderly
Thromboprophylaxis + what is used
low dose anticoagulation to reduce the risk of clotting when in hospital or when going home
LMWH
- E.g. tinzaparin 4500U OR Clexane 40mg OD
- Not monitored
TED stockings (for surgery or if heparin is contraindicated)
Flotron (boot)- Intermittent compression (increases flow) – avoiding stasis component
Sometimes DOAC +/- aspirin (orthopaedics)
when during hospital admission should thrombophylaxis be given
All admissions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis
Risk Assessment for VTE
-
Patient
- Age > 60 years
- Previous VTE
- Active cancer
- Acute or chronic lung disease
- Chronic heart failure
- Lower limb paralysis (excluding acute CVA)
- Acute infection
- BMI > 30
-
Procedure
- Hip or knee replacement
- Hip fracture
- Other major orthopaedic surgery
- Surgery > 30 mins
- Plaster cast immobilisation of lower limb
Treatment for DVT/ PE
Need to be anticoagulated IMMEDIATELY
Thrombolysis - when is its use
- Thrombolysis is only used for life-threatening PE OR limb-threatening DVT
big increase in the risk of INTRACRANIAL HAEMORRHAGE (4%)
factors for risk of recurrence of VTE and long term coagulation
need to assess risk of recurrence and bleeding when considering long term coagulation
risk of recurrence- factors:
- If it occurred after surgery, it has LOW risk of recurrence
- If it has occurred with a non-surgical risk (e.g. COCP, flight), it has a MODERATE risk of recurrence
- If it was idiopathic, it has HIGH risk of recurrence
- They will benefit from long term thromboprophylaxis
which gender has higher risk of recurrence of DVT/PE
- Men have a HIGHER risk of recurrence than women
thrombosis in what part of body has higher reucrrence risk
- Proximal thrombosis (i.e. pelvic or popliteal thrombosis) has a higher rate of recurrence than distal thrombosis (e.g. calf)
when should patients be offered CT scan for thromembolic disease
- All patients > 60 years old with idiopathic thromboembolic disease should be offered a CT scan to check for an underlying cause
SBA 5: Which patient is most likely to benefit from long term anticoagulation after their DVT?
Circumstance of DVT:
- 57 y/o man after flying from Kuala Lumpur
- 27 y/o woman during pregnancy
- 33 y/o woman on COCP
- 77 y/o man after hip replacement
- 30 y/o man after a long walk
- 57 y/o man after flying from Kuala Lumpur
- 27 y/o woman during pregnancy
- 33 y/o woman on COCP
- 77 y/o man after hip replacement
- 30 y/o man after a long walk
remember men have higher risk of recurrence than women
long walk- had an unprecipitated/ idiopathic thrombosis- unlike long flight, pregnancy, COCP, surgery
- 32 y/o woman developed DVT after removal of ovarian cyst. Father and 2 brothers had DVT*
- what should be the next step:*
- Testing for antithrombin deficiency?
- Recommend HRT?
- Continue long term anticoagulation?
- Testing for antithrombin deficiency?
- Recommend HRT
- Continue long term anticoagulation
There is a strong FHx so suggests something is inherited. Continuing longer term anticoagulation may be a good idea if the tests from the antithrombin deficiency come back as positive.
29 y/o man, collapsed at work following PE. No family history
what should be done next
- Test for Factor V Leiden?
- Daily aspirin?
- Continue long-term anticoagulation?
- Heparin injections for long haul flights?
- Test for Factor V Leiden?
- Daily aspirin?
- Continue long-term anticoagulation?
- Heparin injections for long haul flights?
This man had an unprecipitated thrombosis and subsequent PE. Once you have had a PE once, you are likely to see it again. Long-term anticoagulation is the most important thing as this could recur.
Aspirin is popularly used as an anticoagulant, but it is NOT good at this.
67 y/o man present with DVT and weight loss. Started on LMWH
what should be done next
- Abdo-pelvic CT scan?
- Switch to DOAC?
- Switch to warfarin?
- Abdo-pelvic CT scan?
- Switch to DOAC?
- Switch to warfarin?
Cancer is an inflammatory process that can precipitate a thrombosis.
IMPORTANT: ANTICOAGULATION AND RECURRENCE AFTER FIRST VTE + need for long term coagulation
-
Very LOW after surgical precipitant
- No need for long term anticoagulation
-
HIGH after idiopathic VTE (10-20% in 2 years)
- Consider long term anticoagulation
-
After MINOR precipitants (COCP, flights, trauma)
- Usually 3 months adequate
- Longer duration may be dictated by presence of thrombotic and haemorrhagic risk factors
summary
- Heparin and warfarin are anticoagulants with complementary properties
- Knowledge of risks allows appropriate use of thromboprophylaxis and duration of anticoagulant therapy
