Vascular reactions to injury Flashcards
a) what is normal haemostaisis
b) what are platelets
a) physiological response of blood vessels to injury, to prevent blood loss. Accomplished by co-operation between platelets, the coagulation system and andothelial cells. It is limited and controlled by feedback loops and natural antagonists
b) anuclear discs produced by cytoplasmic fragmentation of megakaryocytes in the bone marrow. Their lifespan in the circulation is ~7 days.
Platelet sequence of responses to vascular injury (3 steps), and demonstration of importance of platelets
1) Adhesion - when the endothelelial monoloayer is damaged, platelets adhere strongly to the exposed ECM proteins, especially collagens. This is mediated by von Willebrand factor (vWF), which bridges between glycoprotein IB (GpIb) on the platelet surface and the exposed collagen
2) Activation - following adhesion, the platelets are rapidly activated, involving two events. i) Their shape changes, from discs to flat plates with long processes. This is associated with changes that increase interactions with the coagulation system (modified conformation of GpIIb/IIIa, and movement of negatively-charged phospholipids to the cell surface). ii) they secrete chemical signals by releasing the contents of their granules, including thromboxane A₂ (TxA2), vasoactive amines (5HT) and and ADP. The ADP activates more platelets, increasing their recruitment to the region of vascular injury, while TxA2 induces their aggregation
3) Aggregation - platelet aggregation is initially mediated by the soluble plasma protein fibrinogen bridging between platelets via GpIIb/IIIa complex. As a result, a primary haemostatic plug is formed. This has sufficient internal cohesion to temporarily resist the force of the streaming blood. Simultaneous activation of the coagulaation system leads to the production of thrombin, which causes platelet contraction, where the platelet membranes are drawn into close apposition, with eventual fusion to form a solid mass. Also, thrombin causes the conversion of fibrinogen to insoluble fibrin strands, which bind the platelets in place, creating the stable secondary haemostatic plug, which traps red and white blood cells
Importance of platelets is demonstrated by the effects on haemostasis of reduced platelet number or function, which range from purpura - bleeding from skin capillaries, to spontaneous haemorrhage
Coagulation
a) overview of what it is
b) what initiates
c) significance of the penultimate step
d) pathway
a) result of a cascade of proteolytic reactions, through which inert circulating pro-enzymes are sequentially activated. Each reaction complex comprises an enzyme (an activated coagulation factor), the substrate (a pro-enzyme) and a cofactor to accelerate the reaction. Most reactions are greatly accelerated if carried out on a phospholipid-rich surface, eg on platelets or microparticles (fragments of monocyte or platelet plasma membrane)
b) Initiated by several stimuli. Most important is initiation of the extrinsic pathway by tissue factor derived from damaged tissues
c) the activation of the multi-functional protease thrombin which i) cleaves soluble fibrinogen into insoluble fibrin monomers. ii) activates factor XIII which crosslinks the fibrin monomers to form polymers (strands). iii) activates other coagulation factors (XI, V, VIII), therby producing positive feedback loops. Thrombin also binds to various cell receptors, leading to activation of platelets, endothelial cells and leukocytes (neutrophils and monocytes)
Describe the fibrinolytic system
Accompanies fibrin deposition, and is activated to disassemble the haemostatic plug. The inactive precursor for the fibrinolytic system, plasminogen, is precipitated along with fibrin in the interior of the thrombus. It is converted there to the active fibrinolytic protease plasmin. Important mediators of this process include: factor XIIa and plasminogen activators (eg tissue plasminogen activator and urokinase)
How normal healthy blood vessels prevent haemostasis
a) coagulation inhibition
b) platelet inhibition
c) activation of fibrinolysis
a) i) physical barrier against tissue factor. ii) tissue factor pathway inhibitor (TFPI) which inhibits tissue factor/VIIa complexes. iii) thrombomodulin, expressed on the cell surface, which changes the conformation of thrombin so it is less able to activate coagulation factors and platelets iv) in the presence of thrombomodulin, thombin becomes able to activate protein C. v) endothelial protein C receptor, which binds protein C on the cell surface. In turn, protein C binds its co-factor protein S and together they inhibit the activation of Va and VIIIa. vi) heparin-like molecules, which bind anti-thrombin III and inhibit activation of thrombin, IXa and Xa
b) i) physical barrier against vWF and ECM. ii) prostacyclin (PGI2) and nitric oxide (NO), potent platelet inhibitors
c) production of tissue plasminogen activator (tPA)
Endothelial cell response after injury to a blood vessel
Activated endothelial cells promote haemostasis. Breach of the physical barrier exposes vWF, ECM, tissue factor. The cells down-regulate production of anti-haemostatic molecules (eg TFPI, thrombomodulin, protein C receptor, tPA) and upregulate pro-haemostatic molecules (plasminogen activator inhibitors, PAI)
Thrombosis
a) define and when occurs
b) when can it cause problems
c) how are blood clots different
a) A mass formed from blood constituent within the circulation during life. Composed of fibrin and platelets, with entrapped red and white blood cells. Occurs when the pathological mechanisms of haemostasis are activated inappropriately. It is a pathological process and may have serious consequences
b) may form in a cardiac chabmer or blood vessel (artery, vein or capillary). May cause further damage by obstructing the lumen of vessels in which they form, or by breaking off, travelling in the circulation and obstructing a vessel elsewhere (embolism)
c) formed in static blood. Involves primarily the coagulation system, without interaction of platelets with the vessel wall. Is soft, jelly-like and unstructured and composed of a random mixture of blood cells suspended in serum proteins
Predisposing factors for thrombsis
a) Virchow’s triad
b) detail each catergory listed
a) i) changes in vessel wall. ii) changes in bloow flow. iii) changes in the constituents of blood
b) i) Changes in vessel wall. Due to endothelial cell injury or activation. Ischaemic hypoxia (in the endothelium linging the cardiac chamber in coronary artery disease). Infection (of blood vessel or adjacent tissues). Physical damage (rupture of atherosclerotic plaques, crushing of veins). Chemical damage (lipids, bacterial lipopolysaccharide, toxins from cigarettes). Immunological damage (deposition of immune complexes)
ii) Changes in blood flow. Disruption of laminar flow can cause platelets to come into contact with the endothelium, impaired removal of pro-coagulant factors, imparied delivery of anti-coagulant factors or direct injury or activation of endothelium. Can occur in arteries or cardiac chambers due to turbulence - narrowing (caused by atherosclerosis), aneuryms (abnormal dilations), infarcted myocardium. Can occur in veins due to stasis - failure of the right side of the heart, immobilisation or compressed veins (long flight, bed rest) - most commonly affected veins are pelvic veins, and deep and superficial leg vein
iii) Changes in the constituents of blood. Lead to an increased tendency to coagulate. Specific genetic causes include deficiency of antithrombin III or protein C. Specific acquired causes include - tissue damage (trauma, myocardial infarction), cigarette smoking, elevated blood lipids, oral contraceptive therapy
Components and appearance of thrombi
a) what does it depend on
b) in arteries or cardiac chambers
c) in veins
a) rate of flow at the site of foramtion
b) thrombi are compact masses, granular and firm. They contain laminations (lines of Zahn) composed of pale branching layers of fibrin and platelets and darker layers with more erythrocytes
c) often have a pale head with a long red tail. There is often little evidence of lamination, but tjrombi in veins still have fibrin and platelets, especially in the head. The tail is red due to many enmeshed red cells
Fate of thrombi (6)
i) lysis - breakdown by fibrinolytic system, can be accelerated therapeutically in an attempt to restore blood flow (streptokinase therapy early after myocardial infarction)
ii) propagation - usually in relatively stagnant blood beyond an occluded vein. Propagates in a long tail along the vein towards the heart
iii) stenosis (narrowing) or occlusion (blocking) of vessel
iv) organisation - thrombus induces an inflammatory reaction and subsequent organisation. Partial digestion by enzymes released from leukocytes. Monocyte/macrophage phagocytosis of debris. Overgrowth and ingrowth of endothelium, with formation of new vascular channels. Migration of smooth muscle cells and fibroblasts. Synthesis of ECM, eg collagen. The organised thrombus may be incorporated into the vessel wall, narrowing the lumen. Alternatively, the new vascular channels may anastomose and dilate, eventually restoring blood flow (recanalisation)
v) infection - thrombi can become infected during a transient bacteraemia or from an infection in an adjacent tissue
vi) embolisation
Emboli
a) define
b) types
c) effects
a) an intravascular mass (solid, liquid or gas) carried by blood flow from its point of origin to impact at a distant site
b) thrombus (thromboembolism), fat, air, atheromatous debris, bone marrow and amniotic fluid
c) effects primarily due to stenosis or occlusion of vessels at the site of impaction, causing ischaemia and/or infarction.
Emboli from systemic veins (usually leg or pelvis) or right side of heart will lodge in pulmonary artery (pulmonary embolus). Can cause hypoxia, reduced cardiac output, right heart failure and potentially death
Emboli from left side of the heart or aorta will enter the systemic arterial system and may pass to the brain, spleen, kidney, gut, legs etc. Results may include infarction with subsequent organ failure
