Thrombosis: Aetiology and Management

Question 1

Why are venous thrombosis important

Answer 1

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

Question 2

Consequences of thromboembolism

Answer 2

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

Question 3

Virchow’s triad

Answer 3

Blood
Vessel wall
Blood flow

Question 4

What underpins thrombosis formation

Answer 4

Virchow’s triad

Question 5

Blood factors in virchow’s triad

Answer 5

Viscosity: Haematocrit
Protein/paraprotein, Platelet count

Coagulation system: Triggered by tissue factor, Generates thrombin, Thrombin converts fibrinogen to fibrin (the clot)

Question 6

Procoagulant factors

Answer 6

V
VIII
XI
IX
X
II
Fibrinogen 
Platelets

Question 7

What regulates coagulation

Answer 7

TFPI
Protein C and S
Antithrombin

Question 8

Anticoagulation factors

Answer 8

TFPI
Protein C
Protein S
Thrombomodulin 
EPCR
Antithrombin 
Fibrinolysis

Question 9

What causes thrombophilia

Answer 9

A disturbance in the balance between increased coagulation factors and platelets and decreased fibrinolytic factors and anticoagulant proteins

Question 10

Why is the vessel wall normally antithrombotic

Answer 10

Expresses anticoagulant molecules: Thrombomodulin, Endothelial protein C receptor, Tissue factor pathway inhibitor, Heparans

Does not express tissue factor

Secretes antiplatelet factors: Prostacyclin, NO

Question 11

What causes the vessel wall to become prothrombotic

Answer 11

Infection, malignancy, vasculitis, trauma

Effects: 
Anticoagulant molecules (eg TM) are down regulated
Adhesion molecules upregulated
TF may be expressed
Prostacyclin production decreased

Question 12

What blood flow factors promote thrombosis

Answer 12

Blood stasis promotes thrombosis

Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium

Question 13

Causes of blood stasis

Answer 13

Immobility: surgery, paraparesis, travel
Compression: tumour, pregnancy
Viscosity: polycythaemia, paraprotein
Congenital: vascular abnormalities

Question 14

Pregnancy risk factors for thrombosis

Answer 14

Increased FVIII< fibrinogen
Decreased Protein S
Increased blood flow

Question 15

Malignancy risk factors for thrombosis

Answer 15

Tissue factor on tumour
Inflammation
Increased blood floq

Question 16

Surgery risk factors for thrombosis

Answer 16

Trauma
Inflammation
Blood flow

Question 17

Surgery risk factors for thrombosis

Answer 17

Trauma
Inflammation
Blood flow

Question 18

Principles of preventing VTE

Answer 18

Identifying high risk patients and high risk situations

Question 19

Principles of treating VTE

Answer 19

Prompt diagnosis and inhibition of coagulation

Question 20

Principles of long term prevention of VTE

Answer 20

Assess risk and rebalance coagulation

Question 21

High dose anticoagulation therapy

Answer 21

Therapeutic

Question 22

Low dose anticoagulation therapy

Answer 22

Prophylactic

Question 23

Anticoagulation drugs

Answer 23

Immediate: herparin (unfractionated, LMWH), direct acting anti-Xa and anti-IIa

Delayed: vitamin K antagonists (Warfarin)

Question 24

Mode of admission of herparins

Answer 24

Unfractionated heparin: iv infusion
Low molecular weight heparin: sub cut
Pentasaccharide: sub cut

Question 25

MOA of herparin

Answer 25

All act by potentiating antithrombin Provide immediate effect (eg for treatment of thrombosis) Long term disadvantage - injections, risk of osteoporosis Variable renal dependence

Question 26

Monitoring herparin therapy

Answer 26

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

Question 27

Anti-Xa anticoagulants

Answer 27

DIrect acting anticoagulants Rivaroxaban Apixaban Edoxaban

Question 28

Anti-IIa anticoagulants

Answer 28

Direct acting anticoagulants | Dabigatran

Question 29

Properties of direct acting anticoagulants

Answer 29

``` 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 ```

Question 30

Long-term anticoagulation therapy

Answer 30

Warfarin

Question 31

Features of warfarin therapy

Answer 31

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

Question 32

Monitoring on warfarin therapy

Answer 32

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 ```

Question 33

Anticoagulants increase the risk of....

Answer 33

Bleeding

Question 34

Who is at risk of thrombosis

Answer 34

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

Question 35

Thromboprophylaxis therapy

Answer 35

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)

Question 36

What needs to be dome with all patients admitted to hospital

Answer 36

All admissions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis.

Question 37

What patient factors put the patient at increased risk for VTE

Answer 37

``` Age > 60yrs Previous VTE Active cancer Acute or chronic lung disease Chronic heart failure Lower limb paralysis (excluding acute CVA) Acute infection BMI>30 ```

Question 38

What procedure factors may put the patient at increased risk for VTE

Answer 38

``` Hip or knee replacement Hip fracture Other major orthopaedic surgery Surgery > 30mins Plaster cast immobilisation of lower limb ```

Question 39

What patient factors may put the patient at increased risk of bleeding

Answer 39

``` 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 ```

Question 40

What procedure factors may put the patient at increased risk of bleeding

Answer 40

Neuro, spinal or eye surgery Other with high bleeding risk Lumbar puncture/spinal/epidural in previous 4 hours

Question 41

Treatment of DVT/PE

Answer 41

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

Question 42

When should thrombolysis be used for VTE

Answer 42

Only for life threatening PE or limb threatening DVT Risk of haemorrhage (ICH) ~4% Reduces subsequent post-phlebitic syndrome Indications broadening slowly

Question 43

What determines long-term anticoagulation therapy

Answer 43

Risk of recurrence: morbidity and mortality of recurrence | Risk of therapy (bleeding): morbidity and mortality of bleeding, variation of risks with different therapies

Question 44

Anticoagulation and recurrence after first VTE

Answer 44

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