Haemostasis and Thrombosis Flashcards
How many hospital deaths are caused by PE?
5-10% - 1 in 1000 - 10,000 pa
25,000 deaths pa from hospital related VTE
Incidence doubling each decade
PE’s are preventable but difficult to reverse
What are the consequences of thromboembolism (and how common are they?)
Death - 5% mortality
Recurrence- 20% in first 2 years and 4% pa after
Thrombophlebitic syndrome - Severe TPS in 23% at 2 years, 11% with stockings
Pulmonary hypertension - 4% at 2 years
What increases the risk of thrombosis?
Virchow’s triad:
- Blood - hypercoagulability
- Vessel wall - Sticky and injured
- Blood flow - stasis
What causes Blood to be more prone to coagulation?
- Viscosity from haematocrit/ protein/ paraprotein
- Platelet count high
- Excess pro-coagulant activity
Recite the summarised clotting cascade
Tissue factor and factor 7a increase F9a and the conversion of F10 to F10a
F8a also converts F10 to F10a
F5 a converts prothrombin to thrombin (F2a) which converts fibrinogen to fibrin and increases clotting
Thrombin also has a positive feedback loo on F8 and F5
Which factors are pro coagulant?
V VIII XI IX X II Fibrinogen Platelets
What are the anticoagulants?
Tissue factor pathway inhibitor (TF and 7a inhibitor)
Protein C and S (10a and 5a inhibitor)
Antithrombin (5a and thrombin inhibitor)
Thrombomodulin
EPCR
Fibrinolysis
What happens to the balance of pro and anti coagulants in thrombophilia?
More procoagulants
Less anticoagulants
What happens over time in pts with genetic Thrombosis risk?
As age increases, the risk of thrombosis free survival decreases and this risk is increased in those with genetic defects of thrombosis
Is the vessel wall normally antithrombotic or prothrombotic and why?
Anti thrombotic:
1. Expresses anticoagulant molecules (thrombomodulin, Endothelial protein C receptor, TFPI, heparans)
- Does not express TF
- Secretes antiplatelets like prostacyclin and NO
What causes the vessel wall to become pro thrombotic?
Injury or inflammation:
- Infection
- Malignancy- risk increases with time spent after diagnosis
- Vasculitis
- Trauma
What happens when the vessel wall is in it’s prothrombotic state?
Anticoagulant molecules (eg TM) are down regulated
Adhesion molecules upregulated
TF may be expressed
Prostacyclin production decreased
How does stasis promote thrombosis?
Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium
What are the causes of stasis?
- Immobility- surgery, travel (esp. >12hrs, 4.77 per million), paraparesis
- Compression- tumour, pregnancy
- Viscosity- polycythaemia, paraprotein
- Congenital- vascular abnormalities
A 23 year old woman comes in with a painful leg after a 16 hour flight, a doppler reveals a DVT, what medication could you consider giving them?
Immediate:
- Heparin: unfractionated, LMWH
- DOAC
Delayed:
- Vitamin K antagonist (warfarin)
Through which route are: Unfractionated heparin Low molecular weight heparin Pentasaccharide given?
Unfractionated heparin: IV infusion
LMWH: Sub cutaneous
Pentasaccharie: Sub cutaneous
How do these drugs work:
Unfractionated heparin
Low molecular weight heparin
Pentasaccharide ?
Potentiating antithrombin and providing immediate risk
But need to think about renal disease and long term risk of osteoporosis
Which type of heparin needs to be monitored?
Unfractionated heparin - it has more variable kinetics and dose-response
However in Renal Failure and extremes of weight LMWH should be monitored too
How do you monitor heparin?
Unfractionated: APTT or anti 5 a assay
LMWH: Anti 5a assay
What are the types of DOACs?
Anti 10a (-xabans) and Anti 2a (dabigatran)
What are the properties of a DOAC?
Oral, rapid acting with short half life
Peaks at 3-4 hours, does not require monitoring
Also useful in the long term
Is warfarin Oral?
Yes - oral is good for long term use
How does warfarin work?
Indirectly- prevents recycling of Vit K so takes longer to work
F2/7/9 and 10 fall but so does Protein C & S (which are also Vit K dependent)
How do we monitor warfarin?
INR between 2-3
derived from PT
Which drug is safe in pregnancy?
Heparin
NOT WARFARIN, have to stop by 6 weeks
What is the half life for LMWH, UFH, Warfarin and DOACs?
LMWH - 6 hours
UFH - 1-2 hours
Warfarin - 2-3 days
DOAC - 8-10 hours
How do you reverse heparin, warfarin and DOACs?
Heparin - protamine
Warfarin - factor concentrate/ vitamin K
DOAC- Ab to dabigatran, Xa in development
Who’s at 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 Thromboprophylaxis is used?
Assess ALL patients on admission
LMWH - Tinzaparin 4500u /clexane 40mg OD
- does not require monitoring
TED stockings (surgery or heparin CI)
Flotron (intermittent pneumatic compression to reduce pressure)
Sometimes DOAC +/- aspirin (orthopaedics)
What is included in the patient part of the Risk Assessment for 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 is included in the procedure part of the Risk Assessment for VTE?
Hip or knee replacement
Hip fracture
Other major orthopaedic surgery
Surgery > 30mins
Plaster cast immobilisation of lower limb
What is included in the patient part of the bleeding risk assessment?
Bleeding diathesis (eg haemophilia, VWD)
Platelets < 100
Acute CVA in previous month (H’gge or thromb)
BP > 200 syst or 120 dias
Severe liver disease
Severe renal disease
Active bleeding
Anticoag or anti-platelet therapy
What is included in the procedure part of the bleeding risk assessment?
Neuro, spinal or eye surgery
Other with high bleeding risk
Lumbar puncture/spinal/epidural in previous 4 hours
What is the treatment pathway for DVT/ PE?
Immediate anticoagulation
> Start LMWH
> Stop LMWH when INR >2 for 2 days
OR
> Start DOAC
- continue for 3-6 months
Give an example of a LMWH treatment that may be given for immediate treatment of DVT/ PE
Tinzaparin 175u/kg + warfarin
When would you thrombolyse a DVT/ PE?
Life threatening PE or limb threatening DVT
There is a risk of haemorrhoage (4%) but reduces post phlebitic syndrome
Does the risk of thrombosis if untreated outweigh the risk of bleeding if treated?
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 long do you anticoagulate the patient after first VTE after a surgical precipitant?
No need for long term
How long do you anticoagulate the patient after first VTE that was idiopathic?
You should consider long term
How long do you anticoagulate the patient after first VTE after a minor precipitant such as COCP, flights or trauma?
Usually 3 months adequate
Longer duration may be dictated by presence of other thrombotic and haemorrhagic risk factors
What is heparan?
Makes chemokine gradient across vessel wall
What do PGI2 and NO do?
Vasodilation and reduced platelet aggregation
what is immunothrombosis?
Neutrophils undergo NETosis - neutrophil elastase etc. on top of inflamed endothelium
Inflammation is an important part of thrombosis by activating neutrophils and endothelial cells
Which two risk factors stack?
Oral contraceptive pill
Factor V leiden
Which has a higher risk of thrombosis: FV leiden or Antithrombin deficiency?
Antithrombin deficiency
Which are the Vit K dependent clotting factors?
2, 7, 9, 10
Which condition do we always use warfarin for thromboprophylaxis?
Prosthetic valves
Which has less intercranial bleeding risk, DOAC or warfarin?
DOACs
Men or women: who has a higher recurrence?
Men
What position thrombosis has a higher rate of recurrence?
Proximal (popliteal and above)
Which drug-drug interactions are important?
Lots, carbamazepine, rifampicin
antibiotics and anti epileptics etc.
