Vascular System Disturbances

• This section covers abnormalities in blood flow, tissue interstitial fluid dynamics, and haemostasis.
• Vascular system disturbances can have both local and widespread effects.
• Healthy tissues rely on the circulatory system's ability to deliver oxygen and nutrients while removing waste.
• The vascular system functions like a transportation grid with interconnected components.
• Vertebrate pathology includes hyperaemia, haemorrhage, ischaemia, oedema, and thrombosis.

Hyperaemia

• Characterized as an increased amount of blood in a part of the vascular system.
• Active hyperaemia involves increased blood supply through actively dilating arteries and arterioles, resulting in well-oxygenated, pink tissue.
• Passive hyperaemia is when there's decreased blood drainage through veins and venules, leading to poorly oxygenated, dull red tissue.
• Hyperaemias can be acute (rapidly developing) or chronic (slowly developing) and can be localized or generalized.
• Passive hyperaemia is often referred to as congestion.
• Active chronic hyperaemias do not occur.

Passive Hyperaemia examples

• Tourniquet obstructing blood outflow.
• Congestive heart failure causing blood to 'back up'.

Active Hyperaemia examples (often autonomic neurogenic)

• Inflammation increases nutrient supply, O2, and defense mechanisms.
• Blushing.
• Muscles during exercise.
• Sexual organs.
• Gastrointestinal tract during digestion.
• Small numbers of red blood cells can leak into extravascular tissue, known as diapedesis, distinguishable from haemorrhage via ‘rhexis’.

Haemorrhage

• Defined as the escape of blood from a damaged blood vessel, typically by rhexis (rupture), but can also result from diapedesis in smaller vessels.
• Can occur externally, into a body cavity, or into tissue spaces.
• Nomenclature depends on the location of the haemorrhage.
• Haemothorax: Haemorrhage in the body cavity.
• Haemopericardium: Haemorrhage in the body cavity.
• Haemoperitoneum: Haemorrhage in the body cavity.
• Haemarthrosis: Haemorrhage in the body cavity.
• Haemoptysis: Coughing blood from the lungs.
• Haematemesis: Vomiting blood.
• Haematuria: Blood in the urine.
• Melaena: Bleeding into the GIT.
• Epistaxis: Bleeding from the nose.
• Damage to endothelial cells can cause multiple small haemorrhages on the skin, mucous membranes, or serosal surfaces, referred to as a purpuric tendency.
• Petechiae are tiny pinpoint haemorrhages in the mucus membranes or skin.
• Ecchymoses are larger haemorrhages (up to 2-3 cm), e.g., bruises.

Causes of Haemorrhage include

• Mechanical trauma
• Congenital or acquired vessel wall weakness.
• Toxic damage to endothelium
• Disorders of the clotting mechanism.

Physiological Events After Haemorrhage: Phase 1

• Redistribution of remaining blood.
• Venous return falls.
• Cardiac output is reduced.
• Arterial blood pressure falls.
• Vasomotor centers stimulated.
• Blood supply maintained to brain and respiratory muscles.
• Tachycardia occurs and adrenalin and noradrenalin' released.
• Kidneys release renin.

Physiological Events After Haemorrhage: Phase 2

• Attempt to restore blood volume.
• Blood pressure is still bound to fall.
• Plasma proteins exert osmotic force to pull fluid into circulation.

Physiological Events After Haemorrhage: Phase 3

• Erythropoiesis restores RBC number and the haemoglobin content.

Resolution of Haemorrhage:

• RBCs release haemoglobin (heme + globin).
• Iron is stored as haemosiderin and ferritin.
• Haemosiderin appears as a coarse, yellow-brown pigment in sections stained by H & E - stains intense blue with Perl's Prussian Blue stain, and large amounts impart a brown discolouration to the tissue.
• Macrophages phagocytose debris, RBCs (erythrophagocytosis), and haemosiderin.
• Globin is recycled.
• Fibrinogen converts to fibrin extracellularly to encourage fibroblasts to enter and produce collagen and fibrous tissue (fibrosis).

Oedema

• Oedema is the accumulation of excess extravascular fluids in tissue spaces or body cavities.
• Oedema: Approximately two thirds of the body's water component is intracellular, with the remainder being present in extracellular compartments, particularly as interstitial fluid.
• Non-inflammatory oedema is low in protein and is termed a transudate.
• Fluid that is high in protein and cells is an exudate.
  • This is usually caused by inflammation.

Transudate Vs Exudate

• Protein content: Transudate is low, exudate is high.
• Protein type: Transudate is albumin (low MW). Exudate is as in plasma.
• Fibrin: Transudate is absent and does not clot. Exudate is present as in plasma and clots.
• Specific gravity: Exudate has a high presence of cells. Transudate has low to no presence of cells.
• Cell content: Transudate has low/none. Exudate has many inflammatory cells.

Transudates at specific sites

• Hydrothorax: In the pleural cavity.
• Hydropericardium: In the pericardial sac.
• Hydrocoele: In the tunica vaginalis.
• Ascites: In the peritoneal cavity.
• Anasarca: Generalised subcutaneous oedema.

Primary causes of increased extravascular fluids (oedema)

• a) Increased vascular hydrostatic pressure
  • active hyperaemia e.g. heat
  • passive hyperaemia, e.g. congestive heart failure, venous thrombosis, hepatic cirrhosis, external pressure on vessels from tumours.
• b) Low plasma protein levels
  • Low plasma osmotic pressure.
• c) Lymphatic obstruction
  • Tumour in lymph nodes
  • Removal of lymph nodes may result in impaired removal of extracellular fluid.
• d) Change in control of overall fluid balance
  • Disease in hypothalamus
  • Pituitary, adrenal glands e.g. increased renin-angiotensin-aldosterone secretion; renal hypoperfusion leading to increased tubular resorption of sodium.
• e) Increase in osmotic pressure of interstitial fluid
  • Excess ionic intake (especially Na+ ) coupled with renal insufficiency.
• f) Increased endothelial permeability
  • Neurogenic action of chemical mediators, e.g. allergy.
• Variations of tissue tension in different parts of the body usually determines where oedema collects.
• Muscular activity is essential for lymphatic fluid movement.

Blood Volume Expansion and the Atrial Natriuretic Peptide

• Atrial cardiocytes release atrial natriuretic peptide when there is blood volume expansion.
• ANP exerts effects on fluid and electrolyte balance and on blood pressure.
• ANP causes vasodilation, natriuresis suppression, inhibition of the drinking response, and a fall in atrial pressure.

Ascites in right sided heart failure (RSHF)

• RSHF causes passive hyperaemia of the right side of the circulation
• Congestion of liver, predominantly in periacinar regions
• Increased hydrostatic pressure in sinusoids
• Fluid is forced into Spaces of Disse that line sinusoids
• Fluid drains into lymphatics around portal triads and under the capsule
• Fluid leaks out through the capsule
• Ascites forms
• Increased protein is also leaked leading to some fibrin deposits over liver and throughout ascitic fluid.

Pulmonary oedema in left sided heart failure (LSHF)

• LSHF causes passive hyperaemia of the left side of the circulation
• Congestion of lungs
• Increased hydrostatic pressure in alveolar walls
• Fluid is forced into alveoli
• Pulmonary oedema is formed
• Over time protein and RBCs leak via diapedesis
• Increased numbers of macrophages present to phagocytose debris

Thrombosis

• A compact mass of aggregated platelets and fibrin that build up in the flowing blood stream of a living animal.
• Represents the end result of the blood coagulation, an essential mechanism in normal animals to reduce blood loss following vascular damage.
• Formed by a complex interaction of blood vessel walls, platelets and clotting factors.

Major predisposing causes for thrombosis

• Damage to the endothelial surface.
• Sluggish or abnormally turbulent blood flow.
• Hypercoagulability of the blood.
• Three elements of coagulation include: blood vessel walls, platelets and clotting factors.

Antithrombotic properties of endothelial cells

• Antiplatelet factors include: Physical presence, Production of Prostacyclin (Prostaglandin 12), Nitric Oxide and Adenosine diphosphatase.
• Anticoagulant factors: include: Heparin-like molecules and Thrombomodulin.
• Fibrinolytic factors: t-PA.

Prothrombotic properties of endothelial cells

• Von Willebrand Factor (vWF) this is a cofactor for Factor VIII and assists in platelet activation to collagen.
• Tissue factor this is produced following stimulus endotoxins, tumour necrosis factor or interleukin-1, and activates the extrinsic clotting cascade.
• Inhibitors of Plasminogen Activators these suppress fibrinolysis

Platelets in Haemostasis

• Cellular components of blood which are responsible for maintenance of vascular integrity.
• When an area of endothelium is damaged, an initial platelet plug is formed to minimise blood loss, which is then involved in the formation of a thrombus.
  • Exposure of subendothelial collagen and decreased prostacyclin production by endothelial cells encourage platelets to adhere and aggregate.
    • Adhesion refers to the sticking of platelets to nonplatelet surfaces.
    • Factor VIII/von Willebrand factor are the major cofactors in this process, along with calcium.
    • Once platelets adhere they swell and undergo conformational changes that encourage aggregation of more platelets to platelet surfaces.
• Upon aggregation platelets release various substances.
  • 1. ADP which promotes additional platelet aggregation.
  • 2. Platelet factor 3 (PF3) which participates in the formation of thrombin.
  • 3. Thrombospondin which assists in the adherence of fibrinogen.
  • 4. Platelet factor 4 (PF4) which inhibits the action of heparin and fibrin degradation products.
  • 5. Serotonin which causes vasoconstriction.
  • 6. Thromboxane A2 which causes vasoconstriction and platelet aggregation.
  • 7. Thromboplastin which triggers coagulation pathways.

Coagulation Important features

• Ca++ dependent.
• PT measures extrinsic pathway.
• APTT measures intrinsic pathway.
• Extrinsic pathway is much quicker than intrinsic.
• Both pathways contain factors whose production is dependent upon Vitamin K.
• Most of the coagulation factors are produced by the liver.
• a) Antithrombin III system
  • Glycoprotein serine proteases, ATIII inhibits thrombin (on endothelial surface) + Xa.
• b) Protein C
  • Major regulatory pathway, vitamin K dependent
  • Activated by thrombin binding to endothelial cell receptor thrombomodulin, which prevents the activation of factor V and fibrinogen by thrombin and enables the degradation of factors V and VIII by Protein Ca

Fibrinolysis

• Activation of plasminogen:
  • Intrinsic pathway
  • Tissue activators: endothelium, IV fibrinolysis
  • Leukocytic activators.
  • Micro-organisms
  • Biological fluids: many cell types, tissue fibrinolysis.
• Once formed, a thrombus may: Cause immediate death and be lysed by the fibrinolytic system.
• Plasmin
  • causes lysis of fibrin
  • activates Factor XII (to initiate production of bradykinin)
  • initiates complement cascade.

Embolism

• An embolus is a plug of some material that is transported through the circulation to eventually obstruct the lumen of a vessel too small to allow its passage.
• Emboli may arise from pieces of thrombus which detach and are swept away.
• Emboli may arise from other material e.g. air, fat, neoplasms, parasites.
• The obstruction of a vessel by an embolus may cause severe circulatory problems depending on the site and size of the vessel.
• Thrombosis or embolism may be followed by:
  • Infarction (death) of the tissue if it has an endarterial blood supply.
  • No effect if a collateral circulation exists.
• A very serious complication of both thrombosis and embolism is the presence of microorganisms in the material, referred to as a septic embolus or thrombus.

Difference Between a Thrombus and a Post Mortem Clot

• Thrombus
  • Dry
  • Granular/rough
  • White/Buff
  • Stratified
  • Adhered to Wall
  • Damaged vascular endothelium
  • Composed of fused platelets
  • Flowing Stream
  • Never organised
• Post Mortem Clot
  • Moist
  • Smooth/Shiny
  • Red/Yellow
  • Uniform
  • Unattached
  • Intact vascular endothelium
  • Composed of fibrin with all blood elements
  • Stagnant Column
  • Is organised

Disseminated Intravascular Coagulation (DIC)

• DIC is a serious complication of severe systemic disease.
• Widespread coagulation occurs which depletes platelets and coagulation factors.
• Bleeding tendencies occur as a result.
• It can complicate extensive tissue necrosis and septicaemia etc.