PATHOLOGY- Essentials of general pathology - Haemodynamic disorders Flashcards
What is haemostasis
Process by which blood clots form at sites of blood vessel wall damage/ injury
What are the 2 mutually reinforcing processes in haemostasis
Primary and secondary haemostasis
List the sequence of events in haemostasis when a blood vessel is injured
- Vasoconstriction
- Primary haemostasis (platelet plug formation via exposure of collagen / vWF)
- Secondary haemostasis (fibrin meshwork formation via exposure of tissue factor)
- Clot stabilisation / resorption
What causes vasoconstriction
What is the purpose of vasoconstriction
Neurogenic factor secretion
This acts as a temporary fix, reducing blood flow
what is the purpose of primary haemostasis
Formation of platelet plug
List the steps in primary haemostasis
- Endothelial disruption causes exposure of collagen & VWF on ECM
- Platelets adhere to VWF via glycoprotein 1b
- Activated -> change shape “spike” > ^ surface area
- Secrete granules -> recruit more platelets
- Aggregate to form platelet plug
What is the purpose of secondary haemostasis
Deposition of fibrin meshwork through the coagulation cascade
List the steps in secondary haemostasis
- Tissue factor exposed (normally expressed on sub-endothelial / fibroblast cells)
- Activates coagulation cascade via activation of factor VII - -> thrombin formation
- Thrombin -> cleaves soluble fibrinogen -> insoluble fibrin -> fibrin meshwork
- Thrombin -> also activates more platelets
- RBC entrapment
- Acts to consolidate primary haemostasis
What is the coagulation cascade
Cascade of enzymes going from inactive to active form
List the steps in the coagulation cascade
- Exposed tissue factor activates factor VII to factor VIIa
- This activates cascade
- Prothrombin is converted in to thrombin
- Thrombin
- Converts fibrinogen (soluble) -> fibrin clot (insoluble)
- Activates more platelets
What is clot stabilisation
Platelet aggregates & polymerised fibrin entrap RBCs to form solid clot
How is clotting regulated
Blood dilution of coagulation factors
What is fibrinolysis
- Activated by t-PA from endothelial cells
- Catalyses plasminogen -> plasmin
- Fibrin is degraded by plasmin
What is the role of normal endothelial cells in clot stabilisation and resorption
- Shield blood constituents from TF, VWF, collagen
- Also expresses factors to inhibit coagulation cascade, platelet aggregation and promote fibrinolysis (t-PA)
What happens if endothelial cells in clot stabilisation and resorption become damaged
Lose abilities
Become pro-thrombotic
What is atherosclerosis
Chronic inflammatory / healing response to BV injury
How does atherosclerosis occur
- Stimulus causes endothelial damage which increases permeability
- Lipid (LDL) accumulation due to increase in permeability. Platelet/monocyte adhesion at site of damage
- Macrophage migration and activation. Platelet/macrophages -> smooth muscle recruitment
- Macrophage/smoot muscle lipid uptake and T cell activation
- Increase in smooth muscle/ECM. Atheromatous plaque formed
Describe what can happen after an atherosclerotic plaque is formed
- plaque grows causing critical stenosis
- vessel wall weakening, can develop an aneurysm and rupture
- plaque can rupture exposing VW and tissue factors and including thrombosis by inappropriate activation of primary homeostasis and secondary homeostasis
how can atherosclerosis lead to myocardial ischaemia
Atherosclerotic plaque formed
Plaque ruptures activating inappropriate activation of hemosatsis mechanisms
This results in thrombus formation
What is thrombosis
The inappropriate activation of normal haemostatic mechanisms which results in the formation of a “thrombus”
What is a thrombus
Structured solid mass or plug of blood constituents formed within the heart or blood vessels during life
What 3 factors contribute to thrombosis
What are they known as
Endothelial injury (the dominant mechanism)
Abnormal blood flow
Hypercoagulability
Virchows triad
How does endothelial injury lead to thrombosis
- Severe injury causes exposure of TF/VWF through plaque rupture
- Even if vessel isn’t severely damaged, noxious stimuli (such as physical injury, infection, abnormal blood flow, inflammatory mediators, toxins) can turn normal endothelium in to abnormal endothelium through a pro thrombotic endothelial state
- Endothelial cell activation/dysfunction occurs. Pro-coagulant effects cause a decrease in Thrombomodulin, protein C, tissue factor protein inhibitor. Anti-fibrinolytic causes increases in plasminogen activator inhibitors which causes decrease in t-PA
How does abnormal blood flow load to thrombosis
- Turbulence contributes to thrombosis in the heart and arteries. Stasis generally contributes to thrombosis in veins but sometimes in the heart/arteries, E.g. myocardial infarction/ aneurysms
- Endothelial cell activation -> “pro-thrombotic”
- Disrupts normal ‘laminar’ flow -> platelets interact with / touch endothelium
- Prevents washout / dilution of clotting factors
What is hypercoagulability
Abnormal tendency for blood to clot, typically through alterations in coagulation factor function
Endothelial injury leads to what
Hypercoagulability
Abnormal blood flow
abnormal blood flow leads to what
Hypercoagulability
Endothelial injury
What is the most common cause of hypercoagulability in the inherited form (primary)
Factor V Leiden mutation
What can cause secondary hypercoagulability
Cancer
Prolonged bed rest
Myocardial infarction
What is another name for venous thrombosis
Phlebothrombosis
How does venous thrombosis usually occur
Through stasis as the dominant mechanism
Occurs at site of stasis
Most commonly deep veins of legs (DVT)
How does arterial/cardiac thrombosis occur
- Endothelial injury and / or abnormal flow (turbulence) = dominant mechanisms
- occurs at sites of endothelial injury e.g. atherosclerosis / endocarditis
- occurs at sites of turbulent blood flow e.g. vascular bifurcation / prosthetic valve
After thrombosis has occurred, what things can occur next
- Propagation
- Get larger by accumulation of fibrin/platelets
- Dissolution (via fibrinolysis)
- Organisation & recanalization
- Similar to granulation tissue formation
- In-growth of endothelial cells with formation of new blood vessel channels
Embolisation
Define embolisation
Formation of a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin (little bit breaks off and goes elsewhere)
Define embolism
The impaction of an embolus in a vessel whose calibre is too small to allow the embolus to pass leading to vascular occlusion (the little bit broken too big to fit through, getting stuck)
Almost all emboli are what
Thromboemboli
What are thromboemboli
Embolus derived from part of a dislodged thrombus (the little bit that was broken off)
List other types of emboli (more rare than thromboemboli)
- ATHEROSCLEROTIC
- bits of atherosclerotic plaque are broken off in to bv
- INFECTIVE
- Vegetations infected heart valves, mycotic aneurysm
- TUMOUR
- Fragmentation as tumours penetrate vessels
- GAS EMBOLISM
Chest trauma / iatrogenic (>100 ml) - Rapid decompression during diving -> nitrogen
- AMNIOTIC FLUID
- AF into uterine veins
- FAT EMBOLISM
Trauma -> break of long bones, burns, soft tissue injury, CPR
Where do venous emboli occur
- Venous system (most commonly legs), can lead to pulmonary embolism
Where do arterial/systemic emboli occur
- Arterial system - brain, limbs, organs
- e.g. Heart (AF,MI), aneurysms etc.
What is a paradoxical embolism
When you have an embolus which has arisen in the venous circulation, that travels through the inferior vena cava into the right side of the heart but instead of passing into pulmonary circulation, it goes straight through from venous to systemic circulation (if the pt has a defect in the heart, e.g. hole in heart)
What is a pulmonary embolism
How many deaths caused per year in UK
If untreated, what % is the risk of death
Obstruction of pulmonary arterial vessel by an embolus (usual thromboembolus)
60000
87%
What does the majority of pulmonary embolism result from
Deep vein thrombosis
What happens if there is fragmentation of DVT
- Embolus enters inferior vena cava
- Passes through right heart
- Impaction and occlusion in pulmonary circulation
Blood clots that occlude the large pulmonary arteries are virtually always what in origin
Thromboebolic (DVT)
How common is pulmonary artery thrombosis
Rare
What are the 5 classical histories someone with a pulmonary embolism may have
- 5d post hip replacement
- Sudden onset
- Dyspnoea (shortness of breath)
- Hypoxia
- Tachycardia
What do the effects of a pulmonary embolism depend on
The size of the vessel blocked
What are the effect of large pulmonary vessels being blocked
- Main pulmonary artery
- Straddle bifurcation - “saddle” embolus - death!
- PEs beyond bifurfaction but proximal can also be fatal
- Obstruction of 60% of pulmonary flow = death
- True cause of instantaneous death
What is a block in the main pulmonary artery known as
What does it cause usually
What else can be fatal
Straddle bifurcation causing a saddle embolus
Death (true cause of instantaneous death)
Pulmonary embolism beyond bifurcation but proximal
Obstruction of __ of __ can cause death
60%
Pulmonary flow
What are the effects of smaller vessels being occluded in pulmonary embolism
Dyspnoea (breathlessness)
Pleuritic chest pain (pain on inspiration)
Why do most people not know they have smaller vessel occlusion
Asymptomatic (60-80% clinically silent)
What 2 things does systemic thromboembolism cover
Cardiac
Arterial
Where does systemic thromboembolism occur
Within the arterial circulation
80% of systemic thromboemboli arise from what
Intro-cardiac mural thrombi (myocardial infarction, atrial fibrillation, etc)
Systemic thromboembolism can arise from what else
- Aortic aneursym thrombus
- Atherosclerotic thrombus
- “Paradoxical embolism”
What is the result of systemic thromboembolism
Ischaemic injury (75% to limbs, 10% to brain, 15% to other viscera)
What can a paradoxical embolism have an effect on
Brain, limbs, organs (systemic)
Atherosclerosis, thrombosis and embolism causes damage to organs through what 2 things
Ischaemia and infarction
what is ischaemia
Localised tissue hypoxia resulting from a reduction in blood flow to an organ or tissues
Define hypoxia
A state of reduced oxygen availability in tissues which causes cell injury by reducing aerobic oxidative respiration.
The effects of hypoxia can be what 2 things
Reversible
Result in adaptation
If tissue hypoxia is prolonged it can cause cell death of which type
Necrosis
What causes hypoxia
Inadequate blood oxygenation
-Cardio-respiratory failure
-Lung disease
-Low ambient oxygen (e.g. altitude)
Decreased blood oxygen-carrying capacity
-Anaemia
-Carbon monoxide poisoning
Ischaemia
What is ischaemia most commonly caused by
Obstruction to arterial supply by mechanisms such as severe atherosclerosis, thrombosis and embolism
What is another thing that causes ischaemia but isn’t very common
Obstruction to venous outflow
Non-ischaemic (generalised) hypoxia impairs what
Oxygen supply only
Other metabolites still supplied e.g. glucose
Ischaemia impairs what
- decreases supply of metabolites including glucose
- Glycolytic anaerobic respiration fails due to lack of glucose
- build up of metabolites impairs anaerobic respiration further
Out of non-ischaemic (generalised) hypoxia and ischaemia, which one is worse and why
Ischaemia
Injures tissues faster/more severely
When is cell injury reversible
If limited/short duration
what can be therapeutic to ischaemic tissues
Rapid restoration of blood flow
When is cell injury irreversible
If prolonged/sustained
What is the type of cell death in ischaemic injury
Necrosis
What is tissue necrosis called when caused by ischaemia
Infarction
Define infarction
Tissue necrosis as a consequence of ischaemia (i.e. ischaemic necrosis)
Is treating ischaemia through tissue repercussion a good thing
Yes but only if ischaemia is reversible (e.g. rapid PCI for MI/thrombolysis for stroke)
what happens if ischaemia is treated and it isn’t reversible
Permanent damage
Repercussions of infarcted tissues will have no effect
Is reperfusion of non-infarcted but ischaemic tissues always good?
No
What is ischameia-(reperfusion) injury
Generation of reactive oxygen species by sudden reperfusion of ischaemic (dysfunctional) tissues
Reactive oxygen species generated by inflammatory cells cause further cell damage
Generally, which is better from reperfusion and infarction
Reperfusion
Infarction can be classified morphologically by what
Colour
What are the two types of infarction
RED INFARCTION (HAEMORRHAGIC)
WHITE INFARCTION (ANAEMIC)
When does red infarction occur
Dual blood supply/venous infarction
When does white infarction occur
Single blood supply hence totally cut off
Why are most infarcts wedge shaped
- Vascular supply is “up-steam” or “proximal” in the tissue.
- Deeper into the tissue the vascular branches expand
- If obstruction occurs at an upstream point, the entire down-stream area will be infarcted
What is the type of necrosis usually seen in infarction
Coagulative necrosis
What type if necrosis is seen in brain infarction
Why
Colliquative necrosis
No connective tissue framework
If a person dies suddenly (e.g. massive heart attack) what do you see in the tissues?
~ NOTHING
- NO TIME TO DEVELOP HEMORRHAGE / INFLAMMATORY RESPONSE INTO THE INFARCTED TISSUES
Describe the morphological GROSS and MICROSCOPIC features in myocardial infarction after
A. <24 hours
B. 1-2 days
C. 3-4 daysD.
D. 1-3 weeks
E. 3-6 weeks
Gross
A. Normal
B. Pale red/oedematous
C. Yellow with haemorrhaging edge
D. Pale/thin
E. Dense fibrous scar
Microscopic
A. Normal
B. Oedema with early neutrophil infiltration
C. Coagulative necrosis with macrophage infiltration
D. Granulation tissue formation
E. Dense fibrous scar
What is gangrene
Infarction of entire portion of limb (or organ)
What is dry gangrene
Ischaemic coagulative necrosis only (sterile)
What is wet gangrene
Gangrene with superimposed infection
What is gas gangrene
Superimposed infection with gas producing organism e.g. clostridium perferinges
Ischaemic necrosis is the same thing as what
Infarction
