Anatomy and physiology

• Increase in yellow marrow during ageing restricts sites of haematopoiesis to the axial skeleton and proximal ends of long bones i.e. femur and humerus
• In circumstances of chronic hypoxia, the body can convert yellow marrow back to red marrow to increase blood cell production
• Red bone marrow:

  • Site of haematopoiesis
  • Continues production of all blood cell lineages
  • 3 major cell types exist: erythrocytes, leucocytes and thrombocytes
• Yellow bone marrow:

  • In the hollow (medullary) shaft of long bones
  • Often surrounded by a layer of red bone marrow
  • Contains mesenchymal stem cells which produce cartilage, fat and bone
  • Stores adipocytes to use as energy
• The predominant site of haematopoiesis in the foetus during the second trimester is the liver

  From seven months, the bone marrow takes over and continues to be the predominant site in adults
• ·       In the presence of defective or insufficient haematopoiesis in the bone marrow, expansion of the red marrow may occur

  ·       Haematopoiesis can occur in organs such as the liver and spleen- termed extra-medullary haematopoiesis
• The myeloid lineage gives rise to:

  • Megakaryocyte - platelets
  • Erythroblast - erythrocytes (RBC)
  • Myeloblast - monocytes, neutrophils, basophils and eosinophils
• Lymphoid progenitors give rise to:

  • B lymphocyte - plasma cell
  • T lymphocytes
  • Natural killer cells
• Regulation of haematopoiesis:

  • Erythropoietin (EPO) produced by the kidneys which is essential for the proliferation and maturation of RBC
  • Thrombopoietin (TPO) produced by the liver and is essential for the control of platelet production
• The spleen is the main lymphatic organ - mainly acts as a blood filter, removing old red blood cells.

  Also plays a role in the immune response - important for immunity against encapsulated bacteria
• The thymus is responsible for the development and maturation of T lymphocytes
• ·       The right lymphatic duct is responsible for draining the lymph from the upper right quadrant of the body including the right upper limb

  ·       The thoracic duct is much larger and drains lymph from the rest of the body

  ·       These two ducts then empty into the venous circulation at the subclavian veins
• Virchow's node:

  • Left supraclavicular lymph node
  • Sign of metastatic spread via the thoracic duct - usually GI malignancy
  • Can also be a sign of non-GI malignancies such as lymphoma, breast, oesophageal, pelvic and testicular
  • Right supraclavicular lymph node enlargement tends to be from intrathoracic malignancy - mediastinum, lungs and oesophagus
• INR (prothrombin time) measures the extrinsic and common coagulation pathways
• Warfarin exhibits its anticoagulation effects via the intrinsic and extrinsic pathways in the clotting cascade. This activity occurs through effects on vitamin K-dependent clotting factors
• The extrinsic pathway of the coagulation cascade:

  • Triggered by endothelium damage
  • Tissue factor (III) comes into contact with blood
  • Leads to activation of factor X and therefore activates the common pathway
• The intrinsic pathway of the coagulation cascade:

  • Activated by contact of collagen to clotting factors
  • Thrombin generated from previous activation of the extrinsic pathway also activates the intrinsic pathway
  • Leads to the activation of factor X and therefore activation of the common pathway
• The common pathway of the coagulation cascade:

  • Begins with the activation of factor X to factor Xa via the extrinsic or intrinsic pathway
  • Final stages leads to the formation of thrombin and fibrin
• Virchow's triad implicates three contributing factors in the formation of thrombosis:

  • Stasis of blood flow
  • Endothelial injury
  • Hypercoagulability
• PT/INR assesses the EXTRINSIC pathway – since factor VII pathology is rare, it is better used as a measure of overall clotting. It will, therefore, be affected in anti-coagulant use and liver failure
• APTT assesses the INTRINSIC pathway – this, therefore, measures factors VIII (and vWF), IX, and XI. The most common causes of increased APTT are haemophilia A (VIII), B (IX), C (XI), and possibly von Willebrand’s disease (since vWF pairs with VIII)
• Bleeding time – although no longer used formally – measures the formation of the platelet plug. This will be affected by platelet disorders like von Willebrand’s disease (vWF)
• Heparins make a complex with anti-thrombin III and inhibits coagulation

  Anti-thrombin III binds to and inhibits factor Xa and thrombin- prevents activation of the common pathway

  Monitored using aPTT
• All anticoagulants (warfarin, heparins, NOACs) will increase the PT/INR and the APTT
• Warfarin:

  • Inhibits vitamin K epoxide reductase which is needed for the gamma-carboxylation of vitamin K dependent factors
  • Patients on warfarin will have a specific INR target