L10 Haemostasis, Thrombosis, Embolism

• Haemostasis


  Literally "blood-stop". Definition: the arrest of bleeding.
• Thrombosis


  The formation/presence of a clot within a blood vessel.

  
• Embolism


  An obstruction in a vessel due to a blood clot that gets stuck while traveling through the bloodstream (i.e., a clot on the move).
• Haemostasis


  • Involves a combination of platelets + coagulation

  
• Platelets


  • Normal: platelets stick to damaged blood vessels
  • Important when we have a cut, or to repair constant blood vessel injury in mouth, gut, uterus, skin, etc.

  
• Too much platelet stickiness

  Platelets stick to damaged endothelium, leading to arterial thrombosis

  
• Too little platelet stickiness (low platelets, dysfunctional platelets)

  Bleeding from mucosal surfaces, GI bleeds, menorrhagia, bruising

  
• Coagulation (the jelly component of haemostasis)

  • A fibrin jelly
  • Normal: haemostasis, repairing damage after vascular injury
  • Too much: clot (jelly) forms in veins (e.g., deep vein thrombosis)
  • Too little: bleeding disorder (e.g. haemophilia, anticoagulants)

  
• Haemostasis


  A combination of fibrin clot and platelet aggregates

  
• Platelets: Adhesion & Activation

  Endothelial cells at the site of injury release von Willebrand factor (vWF) which binds to subendothelial collagen and VWF receptors on platelets

  
• Von Willebrand Factor (vWF)


  A protein released by endothelial cells that binds to subendothelial collagen and platelet receptors

  
• Von Willebrand Disease


  The most common bleeding disorder, familial and autosomal dominant, caused by deficiency of VWF leading to loss of platelet function

  
• Thrombocytopenia


  Low platelet count, causes include autoimmune, chemotherapy, drug reactions

  
• Thrombocytopenia symptoms


  • Petechiae
  • Mucosal bleeding
  • Easy bruising
• Coagulation - the jelly

  1. Clotting cascade

  2. The key is the FIBRIN clot at the end
• Haemophilia A


  Classic genetic bleeding disorder, factor VIII deficiency, a male disease
• Acquired factor deficiency


  • Liver disease: fails to synthesise clotting factors
  • Warfarin therapy: blocks synthesis of clotting factors
• Venous thromboembolism


  Excessive coagulation = thrombosis
• If blood sits in a large vein

  It can clot = deep vein thrombosis (DVT)

  
• Factors that increase risk of DVT

  • Decreased movement (after leg surgery, obesity, immobilisation)
  • Pro-thrombotic states (older age, cancer, genetic predisposition)
• Deep vein thrombosis


  Can lead to pulmonary embolism if the clot dislodges and travels to the lungs
• Venous thrombosis


  • Fibrin gel formation (coagulation) is important, anticoagulants that interfere with fibrin formation prevent and treat venous thrombosis, whereas antiplatelet drugs don't

  
• Venous thrombus - microscopic view

  • Laminations: Lines of Zahn (thrombus has formed in flowing blood, vs post-mortem clots)
  • Paler: Platelets + fibrin
  • Darker: Red blood cells

  
• Deep vein thrombosis (DVT)


  Local pain, swelling, often offset by collateral channels
• Complications of DVT


  • Pulmonary embolism (~25%)
  • Post thrombotic syndrome (20-35%)
  • Venous ulceration (~5%)
• Pulmonary Embolism (PE)


  95% arise from DVT in the leg, sole or major contributing cause of death in ~10% acute adult hospital deaths, usually in predisposed patients (cancer, immobilised, hypercoagulable)
• Pulmonary Embolism


  • Presentation & outcome depend on size of embolus, number of emboli, and overall cardiovascular status
• Pulmonary emboli morphology


  • If adequate cardiovascular function AND a small PE: bronchial arterial supply sustains lung tissue, embolus is resorbed over time
  • Inadequate CV function/larger PE: tissue downstream from occlusion is infarcted, wedge shaped haemorrhagic infarcts
  • Multiple emboli over time: pulmonary hypertension & right ventricular failure (cor pulmonale)
• Pulmonary Embolism morphology


  • Saddle embolus: large emboli may become stuck in the major branches of the pulmonary trunk, causing sudden death due to obstruction of blood flow to the lungs or acute right sided heart failure
• 1. dimers


  Fibrin fragments produced by fibrinolysis, usually elevated in DVT and PE but not specific, also elevated in malignancy, infection, advancing age
• Hypercoagulability: Thrombophilia


  Abnormalities of coagulation that predispose to thrombosis, most are associated with venous thrombosis

  
• Acquired Thrombophilia


  • Higher risk: age, prolonged immobilization, surgery, fracture, malignancy, heparin-induced thrombocytopenia (HIT), antiphospholipid antibody syndrome (APS)
  • Lower risk: pregnancy & postpartum, oral contraceptives

  
• Inherited Thrombophilia


  • Common: Factor V variant (Factor V Leiden), Prothrombin variant, Increased levels of coagulation factors
  • Rare: Deficiency of antithrombin, Protein C or Protein S

  
• Anticoagulants for venous thrombosis

  1. Warfarin (blocks formation of factors 2,7,9,10)

  2. Dabigatran

  3. Rivaroxaban

  4. Apixaban

  
• DVT/PE Prophylaxis


  • Anticoagulation for most surgical and many medical inpatients (e.g. low molecular weight heparin)
  • Post-operative ambulation & physiotherapy
  • Compression stockings
• Arterial thrombosis


  • Healthy arterial endothelium is "non-stick", but endothelial injury promotes coagulation and platelet binding, usually associated with atherosclerotic plaque

  
• Arterial thrombosis


  Can cause heart attacks (coronary artery atherosclerosis -> thrombosis -> myocardial infarction), stroke (carotid artery emboli, and cerebral artery thrombosis), leg ischaemia (peripheral vascular disease), intestinal infarction (mesenteric artery atherosclerosis)
• Pharmacological treatment of arterial thrombosis

  • Anti-platelet drugs (e.g. aspirin, ticagrelor, clopidogrel)
  • Anticoagulant drugs (e.g. heparin, low molecular weight heparin)
  • Fibrinolytic therapy (e.g. alteplase, tenecteplase)

  
• Antiplatelet drugs


  Interrupt platelet activation pathways (e.g. thromboxane, ADP receptor)

  
• Atrial fibrillation (AF)


  In AF the atrium is like a "bag of worms" and doesn't pump effectively, clots can form in the left atrial appendage and embolise to the brain causing strokes (~6-8% per year)