Haemostasis and Thrombosis

Question 1

What is the case mortality of VTE?

Answer 1

5%

Question 2

What is thrombophlebitic syndrome?

Answer 2

Post-thrombotic syndrome resulting in recurrent pain, swelling, ulcers etc.

In 23% at 2-years (11% with TED stockings)

Question 3

What can be a complication of PE?

Answer 3

Pulmonary HTN (heart failure with high mortality)

In 4% at 2 years

Question 4

Why is thrombosis important?

Answer 4

Significant sequelae (death is rapid) but is preventable through thromboprophylaxis

May be indicator of underlying disease (cancer)

Question 5

What is Virchow’s Triad?

Answer 5

3 contributory factors to thrombosis:

Blood viscosity
Blood flow
Vessel wall damage

Question 6

What can cause high viscocity of blood?

Answer 6

Increased haematocrit + protein paraprotein or high platelet count

Net excess of procoagulant activity

Question 7

List 4 anti-coagulant proteins in the coagulation cascade

Answer 7

TFPI (Blocks FXa + TF/FVIIa complex)

Protein C (Inactivates FVIIIa + FVa)

Protein S (Inhibits FIXa + co-factor to form activated protein C)

Antithrombin (inhibits FIIa, IXa + Xa)

Question 8

What is the function of endothelial protein C receptors (EPCR) ?

Answer 8

Activation of Protein C
(anticoagulant)

Question 9

What are 4 stimuli for increased haemostasis?

Answer 9

Infection

Vasculitis

Malignancy

Trauma

Question 10

How do the stimuli result in increased haemostasis?

Answer 10

Anticoagulant molecules e.g. Thrombomodulin DOWNregulated

TF expressed

Prostacyclin (anti-platelet) production DECREASED

Adhesion molecules UPregulated

vWF release: platelet + neutrophil capture, neutrophil extracellular traps

Question 11

What is netosis?

Answer 11

Neutrophils releasing DNA, vWF + histones

Activates XII to XIIa

Question 12

In which phenomenon is netosis implicated?

Answer 12

Immunothrombosis

In many disorders, inflammation is sufficient to trigger + drive thrombus formation

Question 13

How does a change in blood flow affect thrombosis?

Answer 13

Can result in accumulation of activated factors

Promotion of platelet adhesion + leukocyte adhesion + transmigration

Hypoxia produces inflammatory effect on endothelium

Question 14

What are 4 types of causes of stasis? Give examples of each

Answer 14

Immobility: long haul flights, surgery

Compression: tumours, pregnancy

Viscosity: polycythaemia, paraprotein

Congenital: vascular abnormalities

Question 15

What is the difference in high dose and low dose anticoagulation?

Answer 15

High dose: therapeutic

Low dose: prophylactic

Question 16

What are 2 types of immediate anticoagulation treatments? What is the MOA?

Answer 16

Heparin: unfractionated + LMWH (Increase anticoagulant activity)

Direct acting anti-Xa + anti-IIa

(Reduce procoagulant activity)

Question 17

What is a class of delayed anticoagulation medication? Give an example

Answer 17

Vitamin K antagonist: Warfarin

(Reduce pro-coagulant activity)

Question 18

How do heparins work?

Answer 18

Immediate effect

Bind to + potentiate ANTI-THROMBIN

Question 19

What is the long term disadvantage to heparins?

Answer 19

Osteoporosis

Question 20

How do DOACs work?

Answer 20

Bind directly to enzyme

Anti-Xa: Rivaroxaban, Apixaban, Edoxaban

Anti-IIa: Dabigatran

Question 21

What are the pharmacodynamics and pharmacokinetics of DOACs?

Answer 21

Oral
Immediate acting: peak in ~3-4 hours
Also useful in long term
Short half life, no monitoring required

Question 22

What are the pharmacodynamics and pharmacokinetics of warfarin?

Answer 22

Oral

Indirect effect: prevents recycling of Vit K
Onset of action is delayed
Levels of II, VII, IX + X fall
Protein C + protein S fall

Question 23

Can you give warfarin in an emergency?

Answer 23

No

Used long term only

Also no point in giving larger dose since it’s delayed regardless

Question 24

What is always important to consider when giving warfarin?

Answer 24

Need to measure INR (derived from prothombin time)

Narrow therapeutic window for each individual

Question 25

Why is dosing warfarin difficult?

Answer 25

Has numerous interactions If high dietary VitK: need more Warfarin Variable absorption Interaction with other drugs: protein binding, competition/ induction of cytochromes Teratogenic: can't be used in pregnancy, must stop within 6w or risk fetal malformation

Question 26

What are 4 strategies for prophylaxis?

Answer 26

LMWH: Tinzaparin or Enoxaparin TED stockings (surgical/ if heparin CI) Intermittent pneumatic compression (increase flow) DOAC +/- aspirin (orthopaedic pts)

Question 27

Why are DOACs preferred over other methods of anticoagulation?

Answer 27

Reduce risk of recurrence + Reduce risk of intracranial bleeding by half compared to other drugs

Question 28

Broadly, what causes thrombophilia?

Answer 28

Increased coagulation factors + platelets Decreased fibrinolytic factors + anticoagulant proteins

Question 29

Which 3 characteristics make the vessel wall antithrombotic?

Answer 29

Express anticoagulant molecules Does NOT express tissue factor Secretes antiplatelet factors

Question 30

Which anticoagulant molecules are expressed on the vessel wall?

Answer 30

Thrombomodulin: makes thrombin anticoagulant Endothelial Protein C Receptor Tissue factor pathway inhibitor Heparans: protein C co-receptor

Question 31

Which anti platelet factors are secreted by the vessel wall?

Answer 31

Prostacyclin NO

Question 32

Which 2 procoagulant molecules are kept out of the blood vessel? (in the sub endothelial tissue)

Answer 32

Collagen Tissue factor

Question 33

What is immunothrombosis?

Answer 33

Active participation of innate immune system in forming a thrombus via distinct cellular + molecular interactions Triggered by recognition of pathogens + damaged cells.

Question 34

How does stasis promote thrombosis?

Answer 34

Activation factors accumulate (rise above critical conc.) Promote platelet adhesion Promote leukocyte adhesion (NET) + transmigration Endothelial cells become hypoxic- inflammatory stimulus, promotes adhesion + release of VWF

Question 35

How do thrombotic risk factors interact?

Answer 35

Genetic, acquired + circumstantial RFs often combine to produce thrombosis May have powerful, unpredictable interactions

Question 36

Deficiency of which factor confers the highest risk of thrombosis?

Answer 36

Antithrombin deficiency

Question 37

How are different forms of Heparin administered?

Answer 37

Unfractionated: IV infusion, monitor APTT LMWH: SC, No monitoring Pentasaccharide: SC, No monitoring

Question 38

Why does renal function need to be considered before giving Heparin?

Answer 38

Don't want anticoagulant effect to accumulate too much

Question 39

What can be given to reverse the effects of each class of anticoagulant?

Answer 39

Heparin: Protamine DOAC: antibody to Dabigatran Warfarin: Vit K/ Prothrombin complex concentrate

Question 40

Which anticoagulant is safe during pregnancy?

Answer 40

Heparin

Question 41

Give 6 groups of patients at increased risk of thrombosis

Answer 41

Medical inpatients: infection, inflammation, immobility Cancer: procoag molecules, inflammation, flow obstruction Surgical patients: inflammation, immobility, trauma Previous VTE, FH, genetics Obese Age \>60

Question 42

Which 6 patient factors must be considered as potential CIs to heparin prophylaxis? (ie increased risk of bleeding)

Answer 42

Bleeding diathesis: Haemophilia, VWD Platelets \<100 Acute CVA in previous month: haemorrhage/ thrombosis SBP \>200 / DBP \>120 Severe liver/ renal disease Active bleeding

Question 43

Which 3 procedural factors must be considered as potential CIs to heparin prophylaxis?

Answer 43

Neuro, spinal or eye surgery Other surgeries with high risk bleeding LP/ spinal/ epidural in previous 4h

Question 44

How are patients risk factors of recurrence classified from highest to lowest based on precipitant?

Answer 44

Idiopathic: HIGHEST- no identifiable cause to remove. Consider long term anticoagulation esp. DOAC Non surgical: cOCP, flight, trauma. 3m +/- longer if high thrombotic RF Surgery: LOWEST- only at risk in that circumstance. No need for long term anticoagulation.

Question 44

How are patients risk factors of recurrence classified from highest to lowest based on precipitant?

Answer 44

Idiopathic: HIGHEST- no identifiable cause to remove. Consider long term anticoagulation esp. DOAC Non surgical: cOCP, flight, trauma. 3m +/- longer if high thrombotic RF Surgery: LOWEST- only at risk in that circumstance. No need for long term anticoagulation.