Introduction to haemostasis – a life-preserving process

Human blood: Red, white cells and platelets
Plasma (55%), contains clotting factors
Cellular component, 45%
Haemostasis – restore vascular integrity, limit infection.

Four key components to clotting:
Primary (the platelet plug), secondary haemostasis and fibrinolysis (the body’s hoovering process!)

Response to incision:
Vascular spasm – vasoconstriction, endothelium initiates
Fibrin mesh – strengthens clot, comes out of solution
Platelet adhesion and aggregation
Coagulation – stabilisation of clot
Fibrinolysis

Platelet life cycle: 7-10 days – fragments off megakaryocyte
Eventually removed by reticuloendothelial system
Platelets activated – increases surface area and becomes like putty.
Platelets recognise sub-endothelial tissue via Von Willebrand factor. v sticky (collagen,basement membrane etc). Platelets degranulate.
Von Willebrand factor – circulates and located in endothelial tissue. VW disease – clotting disorder, excessive bleeding
Tissue factor – thrombin. initiates development of fibrin. Stabilises platelets
Platelet science – v complicated. Lots of molecules they can release. Can remodel and change shape
Platelets adhere, activate and aggregate. Fibrin mesh stabilises.
Platelet acts as template to promote coagulation pathway, reactions leading to fibrin can take place on surface.

Exposure to sub endothelial tissue is required for platelet activation (extrinsic pathway).
Coagulation cascade tightly regulated. Factors turn system.
Fibrinolysis balances system.
13 clotting factors, mostly produced in liver. Named and numbered. Cascade of enzyme managed reactions

Tissue factor: Promotes clotting, by binding factor 7a recognising fibrin development
Tissue damage – thrombin (enzyme) and cascade of clotting: fibrinogen to insoluble fibrin

Extrinsic pathway – tissue factor outside of circulation
Intrinsic pathway – inherent coagulability of blood. Eg cut finger on bench. Blood on bench coagulates as a result of non-physiological contact. Contact coagulation
Coagulation pathway actually more complicated than just having these two arms.
Thrombin burst – tissue factor and 7a complex initiates thrombin enzyme and conversion of fibrinogen to fibrin.
Fibrinolysis: clot limiting, repair and healing mechanism (clot dissolution)
Plasminogen – enzyme, activated by another enzyme (tPA) to Plasmin. Eats clot.
The leftover part is D-Dimer, which can be measured clinically (eg in DVT).
tPA can be mimicked in clot busting medication

The body has natural anticoagulants eg.
Anti-thrombin inhibits thrombin.
Normal Clotting requires equilibrium of all of the above constituents
Can be disregulated by disease – eg infection, bone marrow insufficiency – thrombocytopenia – no platelets formed (results in non blanching rash)
Almost every inpatient takes some form of anticoagulant to prevent DVT

Thrombocytopenia – 450 hypercoagulability.
Bleeding disorders can be inherited (eg. Haemophilia) or acquired (liver disease)
Avoid intramuscular injections in these patients
Haemophilia – haemarthrosis v common. Patients become disabled with arthritis
Lab evaluations: FBC and film, coagulation tests, platelet function (inc VWF)
Blood incubated with reagents (eg calcium collater) until tests applied.
Clotting dependent upon calcium (as a co-factor), hence removal block coagulation
Calcium returned before test. Tissue factor can also be added to measure coagulation.
Prothrombin time (PT): measures extrinsic pathway. add tissue factor (also phospholipid and calcium), should take 11-13 seconds until fibrin forms. If around 20seconds, a clotting factor is lacking.
Activated partial thromboplastin time (APTT) – measures intrinsic clotting pathway. Normal time is 28-44 seconds
These tests don’t show which clotting factor is lacking
Thrombin time (TT): add thrombin. Tests final stage in clotting cascade.

In summary, haemostasis is tightly regulated and involves endothelium, platelets, clotting factors and fibrinolysis. Disregulation results in disease.

Introduction to pharmacology

Introduction to Pharmacology 

Pharmacology is the study of drugs on living systems

Why Pharmacology?

  • Diagnostic skills useless without properly prescribed medication
  • Fractured lower limb > 10 drugs used during process
  • Most errors are due to prescribing errors
  • Patients are better informed – doctors need to be too
  • Drugs are chemicals producing a biological effect
  • Drugs can be endogenous substances, given artificially

Fundamentals of pharmacology:

  • Pharmacodynamics – what drug does to body
  • Pharmacokinetics: what body does to drug: route into body, metabolised where
  • Mechanism
  • Indications: hence Clinical uses
  • Adverse effects
  • Contraindications
  • Eg. Aspirin – NSAID. Anti platelet aggregation properties.
  • The process is the most important thing – the mechanism
  • Aspirin inhibits COX enzymes, which catalyzes the breakdown of arachdonic acid to prostaglandins (PGs)
  • By knowing action of PGs, possible to learn pharmacology and physiology
  • By blocking PGs, GI healing is impaired. Can cause Reye’s syndrome in children and bronchial constriction in asthmatics
  • Long term use: adverse effects influence treatment

Properties of Drugs

  • Tissue selective
  • Chemical selectivity
  • Amplification of action – small dose producing profound effects
  • Drugs act at RECEPTIVE sites – expressed in selective tissues
  • Most drugs act at specific receptors including 4 main types: receptors, enzymes, carrier molecules, ions channels
  • eg B adrenoceptor in heart. The drugs changes action of protein channel, amplifying effect.
  • There are hundreds of thousands of receptors – new receptor = new drug
  • Receptor – target site, which produces cellular response/biological effect
  • Agonist – produces biological effect
  • Antagonist – blocks receptor
  • Occupancy =Affinity – ability to bind (therefore antagonist has affinity, not efficacy)
  • Efficacy – response from drug

Binding – different types:

  • Mostly reversible, weak (hydrogen bonds, van der vaals)
  • Or permanent (aspirin) by covalent bonding
  • Affinity- Reversible binding governed by law of mass action
  • Drug dose based on equilibrium constant (50% of receptors are free, 50% bound to agonist). Level of drug required to reach equilibrium constant describes affinity
  • Each drug has KA (affinity value)
  • Higher affinity means lower dose can be used
  • Affinity give sigmoid curve, as there is finite number of receptors available
  • EC50 – effective concentration giving 50% biological response. (Depends on affinity and efficacy). EC50 is used to compare drug potency
  • Pharmacokinetic properties (how well absorbed) will also affect drug potency
  • This is a basic explanation; because pharmacogenetics will also have an effect (receptor density varies)
  • Remember: receptors amplify signals. You don’t need full occupancy to provide an EC50.

Partial and Inverse Agonist

  • Full agonist – full efficacy
  • Partial agonist used in opioid addict
  • Antagonist – no efficacy
  • Inverse angonist – reduces basal receptor activity (has an action so is not an antagonist). Effect could be to reduce heart rate, for example. Could prevent action of another route

Competitive antagonism

  • Eg. Beta blocker
  • Agonist and Antagonist compete for binding site. Both bind reversibility.
  • Surmountable antagonism – To overcome antagonist, increase concentration of agonist
  • Sigmoid curve shifts to right
  • Non-surmountable antagonism consists of:
  • Non-competitive antagonism – agonist binds to different site to antagonist
  • Irreversible antagonism
  • Competitive antagonism is surmountable

Introduction to Imaging

Introduction to Imaging

  • X-Ray – first image of bones of hand. Silhouette of anatomy.
  • Silhouette sign – bony material silhouetted against air. Lost on chest X-ray with pathology
  • Age of patient important in radiology. Multiple lesions on chest X-ray – most likely secondary.
  • Only 25% of world has access to X-ray
  • First scanner developed in Wimbledon by Godfrey Hansfield – a SGUL graduate. First scan in 1976
  • CT chest = 400 chest X-rays. Particularly important to consider in children. And brain/eyes are particularly radiosensitive. Repetitive exposure give cumulative risk. Risk of cancer with CT chest 1 in 1000 (smoking doubles your risk).
  • Childrens’ doses kept low with ultrasound where possible.
  • CT scanning has evolved due to computer progress.
  • EMI record label funded 1st CT, so The Beatles indirectly helped fund CT scanning
  • Functional CT due to labelled glucose – tumours can be imaged due to glucose uptake
  • PET (functional) and CT (anatomy) scans fused together allows tumour to be staged -PETCT
  • All imaging carries risk, due to energy being imputed to patient (ultrasound and MRI heat, X-ray ionising).
  • 1/3 of admissions are for chest pain. Half don’t have heart. Computed coronary angiography is 99% effective for screening. Very high negative predictive value.
  • In fluoroscopy, user gets dose (cardiologists, interventional radiologists and some surgeons are high risk users)
  • Ultrasound – Ian Donald. Uses sonar (WWII technology) used first in 1950s, published in Lancet. High frequency bell which rings
  • Risk is tissue cavitation
  • Black on image is fluid (transmits), white (reflects), grey (partially reflects).
  • Seeing the anatomy can sometimes give you the diagnosis.
  • Doppler effect can assess patency of blood vessels
  • Moore’s law. Every 10 years, size halves. Ultrasound is now ‘point of care’, can be size of smartphone.
  • Ultrasound can image stomach – eg. Pyloric stenosis in child
  • Ultrasound – high negative predictive value, good for excluding pathology inc fractures in remote locations, due to portability
  • Ultrasound prices £40-£120,000
  • MRI – invented by Peter Mansfield in Nottingham
  • 20% of patients cannot tolerate
  • Protons align due to magnetic field, water has most protons,
  • Magnetic field strength is icreasingtarted with 1tesla, now 3tesla which improves signal to noise ratio
  • Radio frequency added (this causes the noise during the scan), which knocks protons off axis. During time they are knocked off, they emit signal, which can be measured
  • Exquisite resolution. Can see bone bruises, MS plaques, tumour inc blood vessels
  • Cannot perform with pacemaker, metal artefacts, certain heart valves
  • Can image mother in first trimester
  • Shall we image early? – eg locked knee before pt sees surgeon
  • Cost of MRI is coming down, more private providers, hence availability is going up