Pathophysiology Flashcards
Coagulation
3 phases - initiation, amplification, propagation
Initiation:
- Exposed collagen binds PLT and vWF
- Exposed TF binds FVII - which activates FIX and FX
- End result = Va, VIIa, IXa, Xa
Amplification
- Prothrombinase (Va/Xa) and Tenase (VIIIa/IXa) formed
- Tenase activates Xa
- Prothrombinase catalyses Thrombin (II) formation
Propagation
- Thrombin burst leads to fibrin production
- Also generates more Va and VIIIa (for prothrombinase and tenase)
- And XIIIa, which crosslinks fibrin
Inflammation
A pathophysiological mechanism of host defence against harmful stimuli
Tissue injury and infection leads to release of PAMPs and DAMPs
Cells recognise these and release inflammatory mediators, including:
- TNFa
- Il-1
- Il-6
Leading to vasodilation, increased capillary permeability, fever and leucocyte chemotaxis
Outcome is either resolution or chronicity
Trauma-induced coagulopathy
Impaired clot formation
- Activated protein C
- Autoheparinisation from glycocalyx degradation
- Consumptive coagulopathy
- Hypothermia and acidosis
- Haemodilution
Dysregulation of fibrinolysis
- Hyperfibrinolysis
- Fibrinolysis shutdown
Impaired platelet function
- Unclear mechanism ?due to DAMPs
Wound healing
Haemostasis
- as per clotting cascase - initiation, amplification, propagation
- formation of clot
Inflammation
- PLT release PDGF and TGFb
- Neuts and macrophages phagocytose foreign material and bacteria
Proliferation
- Epithelial, endothelial cells and fibroblasts proliferate
- Wound closes by contraction
- Strength is 10% at 1 week and 70% at 3 months
Remodelling
- Takes place over months to years
Reperfusion syndrome
Restoration of blood flow to ischaemic area results in:
- Generation of reactive oxygen species
- And inflammatory infiltrate, leading to
- Endothelial damage
- Cytokine production and
- Toxic metabolites (K+, lactate, myoglobin) washout into systemic circulation
- > SIRS and MODS
Anaphylaxis
Exaggerated systemic response to allergen, characterised by vasodilation, vascular permeability, smooth muscle spasm and cellular infiltrate
An example of type 1 hypersensitivity
Driven by IgE binding to allergen and activating mast cells and basophils, with release of primary mediators (histamine, bradykinin, prostaglandins) and secondary mediators (leukotrienes).
DIC
Acquired consumptive coagulopathy characterised by microvascular thrombosis leading to organ dysfunction.
Exposure of blood to procoagulant susbtances (TF) leads to widespread coagulation and tissue ischaemia. Depletion of clotting factors leads to bleeding.
Diagnosis includes
- Low plt
- Low fibrinogen
- Increased PT and APTT
- Increased D-Dimer
- Schistocytes (haemolysed red cells)
Metastatic cascade
Invasion into basement membrane Intravasation Survival in circulation Extravasation Colonisation
Suture duration
Monocryl - 50% strength at 2 weeks
PDS - 50% at 4 weeks
Vicryl - 50% strength at 3 weeks
Vicryl Rapide
Maxon - 60% at 4 weeks
Shock
A state of systemic hypoperfusion.
3 broad phases:
- Compensated
- Decompensated/reversible
- Irreversible
Multiple aetiologies, broadly classified as:
- Obstructive
- Distributive
- Hypovolaemic
- Cardiogenic
Common pathophysiology is cellular hypoxia due to inadequate oxygen delivery. This leads to:
- Cell membrane ion pump dysfunction
- Intracellular oedema
- Leakage of cellular contents
- Inadequate regulation of cellular pH
This progresses on the systemic level leading to:
- Acidosis
- Lactataemia
- Endothelial dysfunction
- Inflammation
This is compounded by neurohumoral mechanisms to defend central end-organ perfusion at the expense of peripheral perfusion.
- Sympathetic activation and vasoconstriction
- Renin-angiotensin-aldosterone system
MODS
= Alteration in 2 or more organs’ function such that homeostasis cannot be maintained
May be primary (due to inciting tissue injury) or secondary (due to host response)
Quantified by SOFA score • CNS - GCS • Cardiovascular – hypotension, inotrope requirement • Coagulation - platelets • Renal - creatinine • Respiratory - paO2/FiO2 • Liver – bili All scored from 0 - 4
SIRS
- Injury leads to production of proinflammatory cytokines (Il-1, Il-2, Il-6, TNFa)
- These cause fever, sympathetic stimulation, RAS activation, coagulation and complement activation and vasoactive compound release
- Consequent endothelial damage and vascular permeability leads to organ dysfunction
Suture duration
Monocryl
- 50% at 3 weeks
- Absorbed in 3 months
PDS
- 70% at 2 weeks, 50% at 4 weeks
- Absorbed at 6-8 months
Vicryl (Polyglactin)
- 75% strength at 2 weeks, 50% at 3 weeks
- Absorbed in 3 months
Maxon
- similar to PDS
Chromic gut:
- loses strength in 10-14 days
- digested by 2-3 months
Atherosclerosis
- Inciting events include proinflammatory substances in the vasculature, including glycated Hb and LDLs, and shear forces from turbulent blood flow (eg at junctions)
- Endothelial injury leads to accumulation of lipid-laden macrophages.
- Platelet aggregation, fibroblast and smooth muscle activation leads to a raised lesion with a fibrous cap, calcification, lipid-rich necrotic core and intimal smooth muscle hypertrophy
Sepsis definition
“clinical syndrome of organ dysfunction, caused by dysregulated host response to infection”
All sepsis has organ dysfunction by definition
SIRS has fallen out of fashion
qSOFA
quick Sequential Organ Function Assessment
RR >22
Altered mentation
Systolic BP <100
2 or more = high risk
Used to predict mortality, NOT to diagnose sepsis (according to 2017 surviving sepsis guidelines)
SOFA
= Sequential Organ Failure Assessment
6 organ systems scored from 0-4 (C3 R2 L)
- Resp - Pa02/Fi02
- Coag - platelets
- Liver - bili
- Cardio - MAP/vasopressor
- CNS - GCS
- Renal - creatinine or urine output
Score of 2 or more suggests presence of organ dysfunction
Dysfunction in 2 or more = MODS
Sepsis pathophysiology
A dysregulated host response to infection
Triggering infectious agent sets off inflammatory cascade:
- Macrocirculatory changes (nitric oxide)
- Microcirculatory changes (glycocalyx disruption, endothelial dysfunction, microvascular thrombosis)
- Inflammation (SIRS and CARS - dysregulated inflammatory response)
- Coagulation (triggered by cytokines or tissue factor)
- Neurally-mediated immunosuppression
- Mitochondrial dysfunction
Multinodular goitre
Broadly, different types are characterized by disordered response to prolonged thyroid stimulation.
These include dietary iodine deficiency, ingestion of goitrogens (that interfere with iodine trapping or thyroxine synthesis), drugs and inflammation (thyroiditis).
Combination of follicular hyperplasia and involution lead to multinodular goitre. Acini undergo colloid involution, haemorrhage, cystic degeneration and fibrosis, leading to nodule formation.
Portal venous gas
Mucosal breakdown leads to extrusion and intravasation of intestinal gas, with contribution from translocation of gas-forming bacteria
Mode of action and reversal options:
Clopidogrel
Aspirin
Dipyridamole
Ticagrelor
Clopidogrel
- Thienopyridine
- Inhibits platelets by binding to P2Y12 ADP receptor, preventing ADP-induced plt aggregation
Aspirin
- Cyclo-oxygenase inhibition, thus preventing thromboxane A2 formation
Dipyridamole
- inhibits platelet shape change by increasing intracellular cAMP
Ticagrelor
- direct P2Y12 antagonist
Mode of action and reversal options:
Dabigatran Warfarin Rivaroxaban Clexane Heparin
Dabigatran
- Direct thrombin inhibitor
- Reverse with idaricizumab (Praxbind)
Warfarin
- Inhibits vitamin K-dependent clotting factors - 2, 7, 9, 10
- Reverse with prothrombinex, FFP and/or vitamin K
Rivaroxaban
- Direct anti Xa
- No reversal
Clexane
- potentiates antithrombin III, a serine protease inhibitor -> inhibits factor Xa
- less anti-IIa activity than UFH
- No reversal, wears off 6-12h
Heparin
- potentiates antithrombin III, a serine protease inhibitor -> inhibits factor Xa
- more anti-IIa activity than LMWH
- Reverse with protamine
- Wears off in 1-2h
Haemorrhagic shock stages
Alternative is 4 stages (for hypovolaemic/haemorrhagic) - 0-15% (<750 ml) 15-30% (750-1500 ml) 30-40% (1500-2000 ml) >40% (>2000 ml)
Vitamin D metabolism
D3 produced in skin from 7-dehydrocholesterol by action of UV radiation
Liver hydroxylates D3 at 25 position to make 25-OH-D3
Kidney hydroxylates 25-D3 at 1 position to make 1,25-OH D3 - this is the active form
Effects:
- Increase calcium absorption in the GIT
- Promotes osteoblast activity and bone formation
Complement cascade
A series of proteins involved in the innate immune response to antigen. These exist in the serum as precursor molecules - stimuli including antigen-antibody binding, direct microbe binding or mannose-binding lectin. Common result is activation of C3, C5 and formation of the membrane attack complex.
Actions are:
- Formation of membrane attack complex (via the classical pathway)
- Opsonisation for phagocytosis (via the alternative pathway)
- Inflammation, attracting macrophages and leucocytes (via the Lectin pathway)
Calcium homeostasis
Calcium is essential to multiple body processes, including muscle contraction, nerve conduction and cardiac rhythm, and its level is tightly regulated.
PTH increases serum calcium by:
- Increasing conversion of Vit D to its active form in the kidney
- Increasing calcium absorption in the GIT (via vitamin D)
- Reducing calcium loss and increasing phosphate loss at kidney
- Increasing calcium resorption from bone (via production of RANKL from osteoblasts, to increase osteoclast activity)
Calcitonin
- Reduces osteoclast activity
- Increases phosphate retention at kidney
- Increases calcium losses at kidney
Vitamin D
- Increases calcium absorption in GIT
Bilirubin metabolism
- Heme is cleaved to biliverdin by heme oxygenase
- Biliverdin is cleaved to unconjugated bilirubin by biliverdin reductase
- Unconj Bilirubin is insoluble so travels in circulation bound to albumin
- Alb-Bili complex enters hepatic sinusoidal blood, enters space of Disse and dissociates
- Free bilirubin taken up by hepatocytes and conjugated with glucuronic acid, then secreted into bile – if biliary excretion impaired, conj bili can re-enter circulation (causing conj hyperbilirubinaemia and jaundice)
- Conj bilirubin is deconj in gut into urobilinogen
- 10-20% urobilinogen reabsorbed into blood and either secreted in bile or excreted in the kidney
- Remainder converted to stercobilinogen and excreted in stool
Bile acid circulation
- Formed from cholesterol by liver – initially lipid soluble
- Conjugated to glycine or taurine to make them water soluble
- Conjugated bile salts are actively reabsorbed in TI and colon
- Bacteria deconjugate some bile salts to make them lipid soluble, which can be passively reabsorbed in gut
- 90% are reabsorbed and circulated
- 10% lost daily – restored by hepatic synthesis
Pancreatitis
Pathogenesis: excessive trypsin release overwhelms protective mechanisms and catalyses more trypsin activation, as well as other enzymes
• Vascular endothelium is damaged, leading to necrosis
• Dense inflammatory infiltrate worsens injury
• Activated enzymes, microcirculatory impairment and inflammatory mediator release worsen damage
• Not clear why some only get interstitial pancreatitis and some get necrosis
Alcoholic pancreatitis
- Sensitisation of acinar cells to CCK-induced premature activation of zymogens
- Toxic effects of alcohol metabolites such as acetaldehyde and fatty acid ethyl esters
- Protein plugging in pancreatic ducts
Triglyceride pancreatitis
Toxic effect of excessive free fatty acids in pancreatic capillaries
OPSI
Spleen contains numerous antigen-presenting cells and T and B-cells. It is the only organ in which some bacteria (particularly encapsulated bacteria) can be effectively identified and destroyed. This is because they resist antibody binding and opsonisation in the rest of the body.
In the follicle of the white pulp, infectious antigens and blood-borne pathogens are presented by antigen-presenting cells. This process initiates the activation of T-cells and B-cells, which eventually leads to the production of opsonizing antibodies (IgG). After opsonization, macrophages, dendritic cells, and neutrophils phagocytose the antigen.
Asplenism therefore leads to increase risk of overwhelming sepsis, particularly secondary to encapsulated bacteria.
GIST
GIST
How does Radiotherapy work?
Formation of free radicals leads to DNA damage
Tumour cells lack DNA repair mechanisms and so are destroyed, whereas normal cells can repair DNA and recover
Barrett’s
.
Radiation enteritis
Acute effects due to: • Rapid turnover of villous epithelium • Loss of mucosal stem cells in Crypts of Lieberkuhn • Consequent mucosal denudation • Oedema and inflammation • Shortened villi • Decreased absorptive area • Followed by leukocyte infiltration • Crypt abscess formation • Ulceration
Occur within hours of irradiation. Should repopulate within days and symptoms should resolve within 2 weeks
Late effects (>3 months) are due to: • Ischaemic changes • Fibrosis and scarring in submucosa as ulcers heal • Endareritis obliterans • Spasm • Accelerated atherosclerosis
Appendicitis
Luminal obstruction (faecolith, lymphoid hyperplasia)
Colorectal cancer genetic pathways
Molecular pathogenesis of CRC has 3 main pathways (applies to both sporadic and familial) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826728/
Chromosomal instability pathway
Typified by FAP
Essentially the Adenoma-Carcinoma sequence
“A Krazy Disease Process” – APC, KRAS, DCC, p53
Microsatellite stable
Mismatch Repair pathway
Germline or sporadic mutation in DNA mismatch repair genes
Typified by Lynch
Abnormalities accumulate in the microsatellites in DNA – known as MSI-High - making them unstable
Microsatellites = repetitive sequences of DNA throughout genome - give measure of integrity
MMR mutations lead to errors in S phase and microsatellite instability
Seen in 10-15% of sporadic CRC and 95% of Lynch tumours
Hypermethylation/CIMP/Serrated pathway
Aka Hyperplastic/Serrated Polyposis pathway
Epigenetic alterations in DNA resulting in gene silencing
High frequency of methylation of CpG islands – “CpG Island Methylation Phenotype” (CIMP) pathway is seen
BRAF-V600 mutation and absence of KRAS mutation is usually seen
MSI-H, CIMP+ BRAF+ sporadic tumours often arise from serrated polyps
Can affect any gene – methylation of promoters prior to affected gene in the DNA sequence causes epigenetic silencing of that gene
Angiodysplasia
Dilated ectactic submucosal vessels thought to be due to obstruction of smaller vessels in submucosa
Hydatid life cycle
Dogs are definitive host - adult tapeworms (Solices) live in GIT. They lay eggs which are passed in the dogs' stool Sheep and pigs are intermediate hosts. They eat eggs in stool, which hatch in the GIT. The larvae (oncospheres) penetrate intestinal wall and travel in the portal circulation to the liver Here they form a fluid-filled cyst called a metacestode, where protosolices develop Ingestion of infected offal containing metacestodes by dogs completes the cycle. The protosolices evaginate from the cyst and attach to the GIT mucosa, developing into adult tapeworms
Splenomegaly
V: splenic vein thrombosis, haemangiosarcoma, portal hypertension
I: malaria, HIV, abscess, TB
T: rupture/pseudocyst
A: ITP, AHA, Sarcoid, SLE, Felty’s syndrome
M: lysosomal storage disease, amyloidosis
I: hypersplenism
N: lymphoma, leukaemia, secondary deposit, myelofibrosis
C: spherocytosis, elliptocytosis
D: cyst
H Pylori
H Pylori
Gram negative flagellated rod
Well-adapted to survive in stomach – virulence factors include
• Urease – hydrolyses gastric urea to form ammonia – alkaline barrier surrounding organism to protect it
• Spiral shape and flagella help it tunnel through the mucus layer
• Attaches to epithelial cells via adhesion molecules
• Delivers CagA toxin into epithelial cells – these dead cells provide nutrients for H pylori
• Induces gastrin hypersecretion
• Not all H pylori has CagA – much more common in far east – and much more assoc with gastric ca
Several mechanisms to ulcerogenesis
• Increased gastrin secretion in response to meals
• Reduced mucus secretion by goblet cells
• Reduced bicarbonate secretion in duodenum
Pseudomyxoma Peritoneii
= gelatinous ascites from rupture of mucinous tumour
Appendiceal mucinous neoplasms (with rupture) Mucinous adenocarcinoma (appendix, colon, rectum, stomach, pancreas, urachus) Primary ovarian (contentious – may be ovarian mets from appendiceal primary)
