T3 L7: Thrombotic Disorders

• What is Deep vein thrombosis?

  Blood clot

  usually in leg

  
• What are thrombotic risk factors?

  Post operative (especially orhopaedic)

  Hospitalisation

  Cancer

  Pregnancy

  OCP

  Long-haul flights

  Obesity

  IV drug abuse
• What is the presentation of DVTs?

  • unilateral calf swelling / heat / pain / redness / hardness
  • can be asymptomatic / clinically silent
  • Differential diagnosis: cellulitis, baker's cyst, muscular pain
  • potentially fatal if missed

  
• What is investigation of choice for diagnosis of DVT and why?

  Doppler ultrasound

  produces real-time 2D image of soft tissue structure

  colour duplex shows direction of blood flow

  veins are non-compressible by probe

  
• How is the likelihood of DVT assessed?

  high Wells score and positive D-dimer test

  proceed to Doppler U/S scan to confirm DVT diagnosis
• What does the D-dimer test indicate?

  activation of the clotting cascade
• What is the treatment of DVT?

  therapeutic anti-coagulation: heparin

  alternatively DOAC eg rovaroxaban

  ensure adequate GFR

  length: 6 months for initial, life-long for subsequent
• What is Warfarin loading for DVT?

  use oral warfarin if poor renal function

  load patient with oral warfarin for 2-5 days

  monitor using INR
• What is the PE clinical spectrum?

  Micro-emboli: Often asymptomatic

  Clinical PE: pleuritic pain, dyspnoea, haemoptysis

  Massive PE: syncope, death

  
• What are the investigations for suspected PE?

  CTPA scan (CT pulmonary angiogram)

  V/Q scan

  ECG

  Chest X-ray

  
• PE - outcomes

  • 5% mortality rate despite treatment
  • 4% develop pulmonary hypertension
  • Cause of death in 10-30% of in-patient post-mortems
  • Up to 60% have micro-emboli at post-mortem
  • A leading cause of ‘preventable’ death in the western world
  • 25,000 deaths/yr in England
• What are the symptoms and treatment for massive PE?

  Symptoms: signs of shock

  • hypotension, acute dyspnoea, collapse, syncope

  Management: thrombolysis with tPA (Alteplase)

  • tissue plasminogen activator (fibrinolytic)

  IV unfractionated heparin
• What should be considered in young patients with spontaneous VTE (venous thromboembolism)?

  thrombophilia screen

  (increased risk of blood clots)

  causes:

  • deficiency of natural anticoagulants
  • anti-phospholipid syndrome
• What are examples of Anti-thrombotics?

  Warfarin

  Heparin

  Newer agents: Dabigatran, Rivaroxaban

  Anti-platelet drugs

  Fibrinolytic agents (thrombolytics)
• What is warfarin?

  Vitamin K antagonist

  prevents gamma carboxylation of F2, 7, 9, 10

  prolongs extrinsic pathway (prothrombin time, PT)

  monitored by INR (international normalised ratio)
• What is the chemistry of Warfarin?

  inhibits vitamin K reductase

  vitamin K can't be reduced

  
• What does Warfarin inhibit, along with Vitamin K reductase?

  natural anti-coagulants:

  Protein C

  Protein S
• How is Warfarin prescribed?

  patient should be loaded with LMW heparin cover

  early fall in protein C and S occurs within hours and can result in an initial pro-coagulant state

  hence heparin should be continued until INR
• What are interactions of Warfarin?

  beware:

  • drug interactions due to cytochrome p450
  • interaction with alcohol: binge drinking potentiates, chronic alcoholism inhibits

  Also affected by:

  • binding to albumin
  • absorption of Vitamin K from GI tract
  • Synthesis of Vitamin K factor by liver
  • hereditary resistance
• What are the side effects of Warfarin?

  Teratogenic (not suitable for pregnancy - causes developmental defects)

  Significant haemorrhage risk

  Minor bleeding

  Skin necrosis

  Alopecia (autoimmune hair loss)
• How do you reverse Warfarin in the case of a life-threatening bleed?

  give prothrombin concentrate (PCC)

  • contains vitamin K dependent factors

  give Vitamin K

  Fresh frozen plasma FFP
• What is Heparin?

  potentiates anti-thrombin

  irreversibly inactivates F2a (thrombin) and F10a

  administered parenterally

  Two formulations:

  • Unfractionated heparin (IV)
  • LMW heparin (injections)

  safe in pregnancy
• How does Heparin work?

  activates antithrombin

  
• What are the characteristics of unfractionated heparin?

  safe in renal failure (as metabolised by liver - not renally excreted)

  not often used due to inconvenient administration

  reversal by: protamine sulphate

  complications: Heparin-induced thrombocytopenia (HIT)

  • can cause DVT
• What are the characteristics of Low molecular weight (LMW) heparin?

  very convenient due to once daily injections

  not usually monitored

  used for thromboprophylaxis for hospital in-patients
• What are Direct oral anti-coagulants (DOACs)?

  oral alternatives to Warfarin

  no monitoring required

  Two classes:

  • direct Thrombin (F2a) inhibitor, eg dabigatran
  • direct F10a inhibitor, eg rivaroXAban, apiXAban

  same strength as Warfarin + LMW heparin for VTE and AF

  inferior for cardiac valves so should not be used
• What are the characteristics of Rivaroxaban and Apixaban?

  DOACs (direct oral anti-coagulants)

  direct F10a inhibitors (Rivaro-Xa-ban: FXa)

  Indications:

  • VTE prophylaxis
  • treat DVTs and PEs
  • stroke prevention in AF
• What is Dabigatran?

  DOACs (direct oral anti-coagulant)

  direct thrombin inhibitor (2a)

  Indications:

  • VTE prophylaxis
  • treat DVTs and PE
  • stroke prevention in AF

  Can be reversed by Idarucizumab (binds and blocks activity)
• What are some types of anti-platelet drugs?

  Aspirin: cyclo-oxygenase inhibitor

  Clopidogrel: APD receptor blocker

  Dipyridamole: inhibits phosphodiesterase

  Prostacyclin: stimulates adenylate cyclase
• What is Thrombophilia?

  conditions that increase risk of thrombosis

  Inherited causes:

  • Factor V Leiden
  • Deficiency of natural anticoagulants

  Acquired causes:

  • Antiphospholipid syndrome (increased risk of VTE)
• What is the treatment of Thrombophilia?

  Heparin / Warfarin for VTE episodes

  Aspirin in pregnancy