Thrombosis: Aetiology and Management Flashcards
Why are venous thrombosis important
Common
Significant sequelae
PE is the cause of 5-10% of hospital deaths
25000 deaths pa from hospital related VTE
Difficult to reverse and leads to morbidity
Preventable
Consequences of thromboembolism
Death - mortality 5%
Recurrence - 20% in first 2 years and 4% pa thereafter
Thrombophlebitic syndrome (recurrent pain, swelling and ulcers)
Pulmonary hypertension - 4% at 2 years
Virchow’s triad
Blood
Vessel wall
Blood flow
What underpins thrombosis formation
Virchow’s triad
Blood factors in virchow’s triad
Viscosity: Haematocrit
Protein/paraprotein, Platelet count
Coagulation system: Triggered by tissue factor, Generates thrombin, Thrombin converts fibrinogen to fibrin (the clot)
Procoagulant factors
V VIII XI IX X II Fibrinogen Platelets
What regulates coagulation
TFPI
Protein C and S
Antithrombin
Anticoagulation factors
TFPI Protein C Protein S Thrombomodulin EPCR Antithrombin Fibrinolysis
What causes thrombophilia
A disturbance in the balance between increased coagulation factors and platelets and decreased fibrinolytic factors and anticoagulant proteins
Why is 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 causes the vessel wall to become prothrombotic
Infection, malignancy, vasculitis, trauma
Effects: Anticoagulant molecules (eg TM) are down regulated Adhesion molecules upregulated TF may be expressed Prostacyclin production decreased
What blood flow factors promote thrombosis
Blood stasis promotes thrombosis
Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium
Causes of blood stasis
Immobility: surgery, paraparesis, travel
Compression: tumour, pregnancy
Viscosity: polycythaemia, paraprotein
Congenital: vascular abnormalities
Pregnancy risk factors for thrombosis
Increased FVIII< fibrinogen
Decreased Protein S
Increased blood flow
Malignancy risk factors for thrombosis
Tissue factor on tumour
Inflammation
Increased blood floq
Surgery risk factors for thrombosis
Trauma
Inflammation
Blood flow
Surgery risk factors for thrombosis
Trauma
Inflammation
Blood flow
Principles of preventing VTE
Identifying high risk patients and high risk situations
Principles of treating VTE
Prompt diagnosis and inhibition of coagulation
Principles of long term prevention of VTE
Assess risk and rebalance coagulation
High dose anticoagulation therapy
Therapeutic
Low dose anticoagulation therapy
Prophylactic
Anticoagulation drugs
Immediate: herparin (unfractionated, LMWH), direct acting anti-Xa and anti-IIa
Delayed: vitamin K antagonists (Warfarin)
Mode of admission of herparins
Unfractionated heparin: iv infusion
Low molecular weight heparin: sub cut
Pentasaccharide: sub cut
MOA of herparin
All act by potentiating antithrombin
Provide immediate effect (eg for treatment of thrombosis)
Long term disadvantage - injections, risk of osteoporosis
Variable renal dependence
Monitoring herparin therapy
Low molecular weight heparin (LMWH):
Reliable pharmacokinetics so not usually required
Can use anti-Xa assay eg: Renal failure (CrCl<50)
Extremes of weight or risk
Unfractionated heparin
Variable kinetics
Variable dose-response
Always monitor therapeutic levels with APTT or anti-Xa
Anti-Xa anticoagulants
DIrect acting anticoagulants
Rivaroxaban
Apixaban
Edoxaban
Anti-IIa anticoagulants
Direct acting anticoagulants
Dabigatran
Properties of direct acting anticoagulants
Includes anti-Xa and anti-IIa Oral administration Immediate acting –peak in approx. 3-4 hours (cf LMWH) Also useful in long term Short half-life No monitoring
Long-term anticoagulation therapy
Warfarin
Features of warfarin therapy
Given orally
Indirect effect by preventing recycling of Vit K
Therefore onset of action is delayed
Levels of procoagulant factors II, VII, IX & X fall
Levels of anticoagulant protein C and protein S also fall
Monitoring on warfarin therapy
Always essential
Measure of effect is the INR
International normalised ratio (INR)
Derived from prothrombin time
Difficult because numerous interactions: Dietary Vitamin K Variable absorption Interactions with other drugs: Protein binding, competition/induction of cytochromes Teratogenic
Anticoagulants increase the risk of….
Bleeding
Who is at 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
Thromboprophylaxis therapy
Low molecular weight heparin (LMWH): Eg: Tinzaparin 4500u/ Clexane 40mg
Not monitored
Rivaroxaban
TED Stockings (for surgery or if heparin C/I)
Intermittent compression (increases flow)
What needs to be dome with all patients admitted to hospital
All admissions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis.
What patient factors put the patient at increased risk 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 procedure factors may put the patient at increased risk for VTE
Hip or knee replacement Hip fracture Other major orthopaedic surgery Surgery > 30mins Plaster cast immobilisation of lower limb
What patient factors may put the patient at increased risk of bleeding
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 procedure factors may put the patient at increased risk of bleeding
Neuro, spinal or eye surgery
Other with high bleeding risk
Lumbar puncture/spinal/epidural in previous 4 hours
Treatment of DVT/PE
Immediate anticoagulation is essential: start LMWH (e.g. tinzaparin 175u/kg + warfarin) and stop LMWH when INR<2 for 2 days and continue for 3-6 months.
In patients with cancer: continue LMWH and not warfarin
Alternatively, can just start DOAC and continue for 3-6 months
When should thrombolysis be used for VTE
Only for life threatening PE or limb threatening DVT
Risk of haemorrhage (ICH) ~4%
Reduces subsequent post-phlebitic syndrome
Indications broadening slowly
What determines long-term anticoagulation therapy
Risk of recurrence: morbidity and mortality of recurrence
Risk of therapy (bleeding): morbidity and mortality of bleeding, variation of risks with different therapies
Anticoagulation and recurrence after first VTE
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 dictated by presence of other thrombotic and haemorrhagic risk factors
