Haemostasis and Thrombosis Flashcards
What is the case mortality of VTE?
5%
What is thrombophlebitic syndrome?
Post-thrombotic syndrome resulting in recurrent pain, swelling, ulcers etc.
In 23% at 2-years (11% with TED stockings)
What can be a complication of PE?
Pulmonary HTN (heart failure with high mortality)
In 4% at 2 years
Why is thrombosis important?
Significant sequelae (death is rapid) but is preventable through thromboprophylaxis
May be indicator of underlying disease (cancer)
What is Virchow’s Triad?
3 contributory factors to thrombosis:
Blood viscosity
Blood flow
Vessel wall damage
What can cause high viscocity of blood?
Increased haematocrit + protein paraprotein or high platelet count
Net excess of procoagulant activity
List 4 anti-coagulant proteins in the coagulation cascade
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)
What is the function of endothelial protein C receptors (EPCR) ?
Activation of Protein C
(anticoagulant)
What are 4 stimuli for increased haemostasis?
Infection
Vasculitis
Malignancy
Trauma
How do the stimuli result in increased haemostasis?
Anticoagulant molecules e.g. Thrombomodulin DOWNregulated
TF expressed
Prostacyclin (anti-platelet) production DECREASED
Adhesion molecules UPregulated
vWF release: platelet + neutrophil capture, neutrophil extracellular traps
What is netosis?
Neutrophils releasing DNA, vWF + histones
Activates XII to XIIa
In which phenomenon is netosis implicated?
Immunothrombosis
In many disorders, inflammation is sufficient to trigger + drive thrombus formation
How does a change in blood flow affect thrombosis?
Can result in accumulation of activated factors
Promotion of platelet adhesion + leukocyte adhesion + transmigration
Hypoxia produces inflammatory effect on endothelium
What are 4 types of causes of stasis? Give examples of each
Immobility: long haul flights, surgery
Compression: tumours, pregnancy
Viscosity: polycythaemia, paraprotein
Congenital: vascular abnormalities
What is the difference in high dose and low dose anticoagulation?
High dose: therapeutic
Low dose: prophylactic
What are 2 types of immediate anticoagulation treatments? What is the MOA?
Heparin: unfractionated + LMWH (Increase anticoagulant activity)
Direct acting anti-Xa + anti-IIa
(Reduce procoagulant activity)
What is a class of delayed anticoagulation medication? Give an example
Vitamin K antagonist: Warfarin
(Reduce pro-coagulant activity)
How do heparins work?
Immediate effect
Bind to + potentiate ANTI-THROMBIN
What is the long term disadvantage to heparins?
Osteoporosis
How do DOACs work?
Bind directly to enzyme
Anti-Xa: Rivaroxaban, Apixaban, Edoxaban
Anti-IIa: Dabigatran
What are the pharmacodynamics and pharmacokinetics of DOACs?
Oral
Immediate acting: peak in ~3-4 hours
Also useful in long term
Short half life, no monitoring required
What are the pharmacodynamics and pharmacokinetics of warfarin?
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
Can you give warfarin in an emergency?
No
Used long term only
Also no point in giving larger dose since it’s delayed regardless
What is always important to consider when giving warfarin?
Need to measure INR (derived from prothombin time)
Narrow therapeutic window for each individual
Why is dosing warfarin difficult?
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
What are 4 strategies for prophylaxis?
LMWH: Tinzaparin or Enoxaparin
TED stockings (surgical/ if heparin CI)
Intermittent pneumatic compression (increase flow)
DOAC +/- aspirin (orthopaedic pts)
Why are DOACs preferred over other methods of anticoagulation?
Reduce risk of recurrence +
Reduce risk of intracranial bleeding by half compared to other drugs
Broadly, what causes thrombophilia?
Increased coagulation factors + platelets
Decreased fibrinolytic factors + anticoagulant proteins
Which 3 characteristics make the vessel wall antithrombotic?
Express anticoagulant molecules
Does NOT express tissue factor
Secretes antiplatelet factors
Which anticoagulant molecules are expressed on the vessel wall?
Thrombomodulin: makes thrombin anticoagulant
Endothelial Protein C Receptor
Tissue factor pathway inhibitor
Heparans: protein C co-receptor
Which anti platelet factors are secreted by the vessel wall?
Prostacyclin
NO
Which 2 procoagulant molecules are kept out of the blood vessel? (in the sub endothelial tissue)
Collagen
Tissue factor
What is immunothrombosis?
Active participation of innate immune system in forming a thrombus via distinct cellular + molecular interactions
Triggered by recognition of pathogens + damaged cells.
How does stasis promote thrombosis?
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
How do thrombotic risk factors interact?
Genetic, acquired + circumstantial RFs often combine to produce thrombosis
May have powerful, unpredictable interactions
Deficiency of which factor confers the highest risk of thrombosis?
Antithrombin deficiency
How are different forms of Heparin administered?
Unfractionated: IV infusion, monitor APTT
LMWH: SC, No monitoring
Pentasaccharide: SC, No monitoring
Why does renal function need to be considered before giving Heparin?
Don’t want anticoagulant effect to accumulate too much
What can be given to reverse the effects of each class of anticoagulant?
Heparin: Protamine
DOAC: antibody to Dabigatran
Warfarin: Vit K/ Prothrombin complex concentrate
Which anticoagulant is safe during pregnancy?
Heparin
Give 6 groups of patients at increased risk of thrombosis
Medical inpatients: infection, inflammation, immobility
Cancer: procoag molecules, inflammation, flow obstruction
Surgical patients: inflammation, immobility, trauma
Previous VTE, FH, genetics
Obese
Age >60
Which 6 patient factors must be considered as potential CIs to heparin prophylaxis? (ie increased risk of bleeding)
Bleeding diathesis: Haemophilia, VWD
Platelets <100
Acute CVA in previous month: haemorrhage/ thrombosis
SBP >200 / DBP >120
Severe liver/ renal disease
Active bleeding
Which 3 procedural factors must be considered as potential CIs to heparin prophylaxis?
Neuro, spinal or eye surgery
Other surgeries with high risk bleeding
LP/ spinal/ epidural in previous 4h
How are patients risk factors of recurrence classified from highest to lowest based on precipitant?
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.
How are patients risk factors of recurrence classified from highest to lowest based on precipitant?
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.
