Cardiovascular disease Flashcards
Haemostasis
Appropriate response to blood vessel injury
Cooperation between platelets, coagulation system and endothelium
Thrombosis
Formation of a thrombus following inappropriate activation of haemostat mechanisms
Platelet response to vascular injury stages
Adhesion
Activation and secretion
Aggregation
Adhesion
Injury to endothelium exposes ECM so can bind to Gp1b on the platelet via vWf
Activation and secretion
Shape change of the platelets from discs to plates to cover more surface area via modification of GpIIb/IIIa
Secretion of alpha and dose granules to release TXA2, ADP, Ca2+ etc for clotting
Aggregation
Bridging between platelets via GpIIb/IIIa cross links by fibrinogen to give primary haemostat plug
Converted to secondary haemostat plus by action of thrombin on fibrinogen to give fibrin
Where do coagulation system reactions happen
On phospholipid rich surfaces e.g platelets, Microparticles
Convergence of the coagulation system
On the activation of factor X; by Factor VIIa (extrinsic), VIIIa and IXa
Activation of prothrombin
Xa, Va and Ca2+ as cofactor
Haemophilia A
Factor VIII deficiency
X linked
Fibrinolytic system
Plasminogen activated to plasmin by tPA, streptokinase, XIIa
Plasmin can break fibrin down into soluble D dimers
Anti-thrombotic
NO
PGI2
Thrombomodulin (binds thrombin)
Protein C
Pro-thrombotic
wVF
Tissue factor
Microparticles
Thromboplastin
Virchow’s triad
Changes in vessel wall
Changes in blood flow
Changes in blood constituents
Changes in blood flow
In veins: stasis due to slow flow
In arteries: turbulent flow; can directly damage the vessels
Arterial thrombus appearance
Compact, granular, firm
Laminations called lines of Zahn
Venous thrombus appearance
Pale head with long red tail pointing towards hear
Harder to see laminations
Blood clot compared to thrombus
Can arise outside of circulation
Only involves coagulation system
Softer
Fate of thrombi
Lysis Propagation in stagnant blood Stenosis/vessel occlusion Organisation Infection Embolisation
Organisation of thrombi
Retraction of the thrombus by WBCs releasing enzymes, ingrowth of smooth muscle cells and fibroblasts, growth of endothelium, ECM synthesis
Then can be pulled into vessel wall
Or form new vessels through it
Embolus
Intravascular mass carried by blood flow to impact at distant site
Emboli from systemic veins or R side of heart
Lodge in pulmonary artery cause hypoxia, heart failure,,
can cause myocardial hypertrophy
Emboli from L side of heart or aorta
Go to brain, gut, kidney
Atherosclerosis
Disease affecting the intimacy of medium and large arteries
Focal thickening called plaques made of fibrous tissues and lipids associated with necrosis and inflammatory cells
LDL
Delivers cholesterol to the tissues
Native LDL receptor pathways
Hepatocytes mainly
Transcription regulated by negative feedback by cholesterol levels
Scavenger receptor pathway for LDL
By macrophages to take up modified lipoprotein
No -ve regulation so get uncontrolled cholesterol accumulation to form foam cells
Dyslipoproteinaemia
Abnormality in constitution/concentration of lipoproteins in the blood
May be inherited e.g FH
Secondary e.g from diabetes mellitus
Atherogenesis
Process by which atherosclerosis occurs
Chronic inflammatory process with prolonged endothelial injury response
Activated macrophage effects
Endothelial cell activation via IL-1 and TNFalpha Recruiting monocytes Activating SMCs Modify ECM with collagenase Oxidise/ingest lipoproteins Antigen presentation
Vascular smooth muscle
Activated by macrophages via growth factors
Proliferate and migrate from media to intima
Change from contractile to synthetic cells and secrete ECM and remodelling enzymes
Lipoprotein contribution having been oxidised in plaques
To local T cell response
+ act as chemoattractant for monocytes
Structure of plaque
Fibrous cap with collagen, SMCs, macrophages, T cells
Lipid core with foam cells, necrotic core, extracellular lipid
Shoulder has lots of angiogenesis so prone to haemorrhage
Ischaemia
Inadequate local blood supply to an organ due to insufficient quantity of blood (rather than quality)
Infarctions
Necrosis due to ischaemia
Causes of ischaemia
External stenosis Internal stenosis Spasm Capillary blockage Shock
Causes of capillary blockage
Cerebral malaria
Sickle cell disease
Types of shock
Cardiogenic
Hypovolaemic
Septic
Anaphylactic
Reversible morphological changes
Swelling, membrane blebs, chromatin clumping
Irreversible changes
ER disintegration, pyknosis (nuclear shrinkage), lysosome rupture
Predominan cytoplasmic change if ischaemia is cause
Eosinophilia (rather than nuclear fragmentation)
Cell susceptibility to hypoxia
Neurons > renal tubule epithelium > myocardium > skeletal muscle > macrophages, fibroblasts
Ischaemic reperfusion injury
Restoring blood flow can
- Allow generation of fresh mediators of injury
- Initiate acute inflammation via delivery of immune cells
Macroscopic shape of infarcts
conical in 3D
wedge in 2D
Red infarct
Due to blood in infarcted tissue
Ischaemia due to venous occlusion, so blood still enters from artery
Or in spongy tissue like lungs that don’t resist blood infiltration
Or those with collateral supply
Pale infarct
Tissue is solid so blood doesn’t enter
Pale with red margins due to vasodilation
Fibrinous exudate on surface and granulation tissue
Septic infarcts
Happen in lung
Check if anywhere else
Cystic infarct
Liquefication necrosis and cyst formation e.g in brain
Myocardial infarction
Mainly LV
Due to coronary artery atherosclerosis
Pale infarct
Pericardial surface gets fibrin deposition (fibrinous pericarditis can happen)
Mural thrombosis
Where a thin layer of scar tissue forms at apex of heart due to an infarct
This isn’t functional so causes turbulent flow and can get thrombosis (this LV thrombus may become infected)
Anaemia
Reduced total mass of circulating red cells
Adult haemoglobin major form
HbA alpha2beta2
Fetal haemoglobin form
HbF alpha2gamma2
Main causes of anaemia
Impaired RBC generation
Increased haemolytic
Blood loss
Megaloblastic anaemia
B12 or folate deficiency
Impaired thymidine production causing defective cell division; but still get RNA/protein production
Megaloblasts; abnormally large erythroblast
Macrocytosis; larger RBCs
Neutrophils have hyperhsegmented nuclei
Right shift on price jones
B12 absorption
Binds haptocorrin (from salivary glands) in the stomach which protects it from stomach acid Pancreatic enzymes digest haptocorrin in duodenum Binds intrinsic factor; IF receptors in ileum absorb complex Transported in the blood by transcobalamin
Folate absorption
Taken up in diet linked to fpolyglutamic acid
Absorbed in duodenum, jejunum, prox small bowel as methyltetrahydrofolate
B12 storage
In liver for 5 years
Folate storage
For 3 months
Iron deficiency anaemia
Females need 15mg per day
Males need 7mg per day
Iron absorption
In duodenum and small bowel
Taken up by mucosal cells and transported out using ferroportin
Negative feedback based on inhibitory hepcidin
Haemoglobinopathies
Structural abnormalities: Sickle cell disease
Diminished production: thalassaemia
Beta thalassaemia
Major: B0/B0, B+/B+, B0/B+
Minor: B0/B, B+/B
Can be loss of chain or inadequate synthesis
Genes are on chromosome 11
Alpha thalassaemia
Due to deletion of 1 to 4 copies of the gene
Genes are on chromosome 16
