Blood Flashcards
Which oxygen molecule binds to haemoglobin the easiest?
4th and last one, as quaternary structure changes as each molecule of oxygen is added and makes it progressively easier for more molecules to bind
Which factors can cause a rightward shift of the oxygen dissociation curve and therefore haemoglobin has a lower affinity for oxygen?
CADET! CO2 Acid 2-3-DPG Exercise Temperature
What is the Bohr effect?
In acidic conditions, oxygen dissociation curve shifts right and so Hb ha a reduced affinity for oxygen
What is the Haldane effect?
Increasing oxygen binding to Hb decreases affinity for CO2 and H+ ions by modifying quaternary structure
What is inflammation?
Protective mechanism
Rid body of cause of injury
Remove debris and tissue damage secondary to injury
What can cause excessive inflammation?
Inappropriately triggered eg rheumatoid arthritis
Poorly controlled eg abscess - leakage of enzymes from cells
What can cause inadequate inflammation?
Immunodeficiency eg AIDS/HIV
What are the beneficial effects of inflammation?
dilution of toxins entry of antibodies fibrin formation to initialise repair nutrients and oxygen deliver neutrophils stimulation of the immune response entry of drugs
What problems can inflammation cause?
destruction of normal tissue swelling blockage of tubes loss of fluid pain inappropriate inflammation
What 6 things can cause inflammation?
Microbes Foreign bodies Dead cells Allergens Physical trauma and damage Chemical injury
What are the 3 phases of acute inflammation in first 48 hours?
Oedema
Neutrophils
Monocytes/macrophages
What are the 3 hallmark features of chronic inflammation?
Ongoing inflammation
Ongoing tissue destruction
Ongoing tissue repair
What are the 5 cardinal signs of acute inflammation?
Rubor - red Tumor - swelling Calor - heat Dolor - pain Functio laesa - loss of function
How does a tissue injury lead to oedema?
Increased blood flow to area due to opening of capillary beds
Dilation of blood vessels so decreased velocity of flow
Increased leakiness of microvasculature due to squamous endothelium retraction
Plasma proteins and leukocytes infiltrate area
What happens to lymphatics during inflammation?
Increase drainage of excess fluid
Proliferate
Which leukocytes are recruited in acute inflammation?
Neutrophils
What are the 3 phases of cellular changes that occur in acute inflammation?
Recruitment - delivery and extravasation of leukocytes
Accumulation
Activation - recognition of microbes and necrotic tissue, removal of stimulus
Which part of acute inflammatory response can lead to tissue injury?
Activation of leukocytes
What are the 4 stages of recruitment and migration of neutrophils?
Margination
Adhesion
Emigration
Chemotaxis
What is margination?
Dilation of vessels - turbulent flow allows WBC to come into contact with endothelium
Stagnation in the microcirculation displaces cells from the central axial
flow
Rolling occurs in unaffected area due to low affinity receptors
What is adhesion?
In areas of injury, endothelial cells possess high affinity receptors (integrins) and so neutrophils adhere to these receptors. Chemokines at injury site activate integrins
What happens in the process of emigration of neutrophils?
Neutrophils secrete enzymes to digest the basement membrane which allows them to invade the tissue
What is chemotaxis?
Chemokines induce movement of neutrophils. Area of high concentration of chemokines is where most damage is so neutrophils move down concentration gradient
How do neutrophils recognise dead tissue or foreign material?
Directly via mannose receptors
Indirectly via opsonins & Fc and C3b receptors
What is opsonisation?
Marking a foreign body for destruction by phagocytosis
How does neutrophilic phagocytosis occur?
Recognition and attachment
Engulfment
Phagosome fuses with lysosome
Oxygen dependent (free radicals) or independent (enzymes) system degrades microbes
Which microbe can survive neutrophil phagocytosis?
Mycobacterium tuberculosis
What part of chronic inflammation can cause scarring?
Fibrous repair
What changes occur that lead from acute to chronic inflammation?
Angiogenesis Mononuclear cell infiltrate Fibrosis (scar) Progressive tissue injury Collagen deposition Loss of function
What are the 4 morphological patterns of inflammation?
Serous - blister
Suppuration - large amount of pus, abscess
Fibrinous - large increase in vascular permeability allows fibrin to pass through. Fibrinous exudate deposited
Ulcers - exposure of lower layers of epithelium
What are the 8 cell derived mediators of inflammation?
Vasoactive amines Arachidonic acid metabolites Platelet activating factor Reactive oxygen species Nitric oxide Cytokines and chemokines Lysosomal constituents Neuropeptides
What are prostaglandins, leukotrienes and lipoxins?
Arachidonic acid metabolites involved in inflammatory process
Which arachidonic acid metabolites cause vasodilation?
Prostaglandins
What do thromboxane A2 and leukotrienes C4, D4 and E4 do?
Cause vasoconstriction
Which cell derived mediators are important in anaphylaxis?
Vasoactive amines - histamine and serotonin
What feature of vasoactive amines makes them rapid acting?
Released from preformed vesicles
What do vasoactive amines do?
Cause dilation of arteries and arterioles
Increased permeability of venules
What does platelet activating factor do?
Platelet aggregation
Vasoconstriction
Bronchoconstriction
Increased AA production
What do reactive oxygen species do in inflammation?
Destruction of ingested particles
Increase chemokines, cytokines and adhesion molecules
Destruction of tissues
What effects does NO have on inflammation?
Control mechanism
Reduces adhesion of leukocytes and platelets
Vasodilation
What do chemokines do?
Promote inflammation and repair
Systemic manifestations - fever, decrease appetite, increase sleep
What is the membrane attack complex?
Complement system c5-9 punches hole in membrane so cell loses equilibrium control and is lysed
In what 3 ways can complement be activated?
Alternative pathway - opsonisation
Classical pathway - antibody
Lectin pathway - mannose binding
What does complement C3b do?
Deposited on microbe
Recognised by phagocyte receptor and phagocytosed
C3a fragment recruits and activates leukocytes
Why is factor XII important?
Activates multiple systems which work together Clotting cascade Complement cascade Kinin cascade Fibrinolytic system
Describe the cycle of chronic inflammation
Recruitment of neutrophils and macrophages
IFN-y activate macrophages
Antigen presentation to T cells - cytokines
T cells release IFN-y
T cells are activated and release TNF, IL17 and chemokines
Further leukocytes are recruited
Macrophages are important in which parts of chronic inflammation?
Continuing inflammatory response
Starting process of repair
What cell mediators cause shock?
Massive quantities of TNF and IL1
When do we see chronic inflammation?
Persisting infection - h pylori gastric ulcer, viral hepatitis, TB
Chronic/autoimmune - bronchitis, crohns, rheumatoid
Foreign material - suture, silica
Inadequate immune response - HIV
Inadequate blood supply - leg ulcer, bed sore
Name a factor that favours continuing ulceration
Insufficient perfusion
When are eosinophils present?
Reactions mediated by IgE and parasitic infections
What are possible outcomes of chronic inflammation?
Atrophy Metaplasia Repair Scarring with dysfunction eg cirrhosis in viral hepatitis Catastrophe eg perforated gastric ulcer
What is lymphoid hyperplasia?
Swollen lymph nodes
What can a C reactive protein (CRP) measurement be used for?
Measure levels of acute inflammation
Name 4 functions of the immune system
Infection and immunity
Inflammatory process
Removal of senescent cells
Defence against neoplasia
Give 3 types of immune disorder
Auto immune
Hypersensitivity
Immunodeficiency
What is serology?
Antibody detection after infection
What is a vaccine?
Prophylactic treatment against infection
What is an antigen?
Substance capable of inducing a specific immune response
Name 3 types of antigen
Microbes, neoplasms and foreign tissue
Give 3 examples of PAMPs (pathogen associated molecular patterns)
Bacterial lipopolysaccharide
Peptidoglycan
Flagellin
Antigens with PAMPs are most likely targeted by which mechanisms?
Innate
Which branch of the immune system provides the immediate response?
Innate
What advantages does the adaptive immune system provide?
Antigen presentation - specific
Clonal selection
Immunological memory
What parts make up the innate immune system?
Epithelial barriers Phagocytes Dendritic cells - antigen presenting cells Complement Natural killer cells
What parts make up the adaptive immune system?
B lymphocytes –> plasma cells, memory cells –> antibody production
T lymphocytes –> helper, memory, suppressor and cytotoxic
What are neutrophils?
Polymorhonuclear phagocytes
First line of defence of innate immune system
What are monocytes and macrophages?
Mononuclear phagocytes
Adaptive antigen presenting cells
What do basophils and mast cells do?
Inflammatory and hypersensitivity responses
What constitutes mucosa associated lymphoid tissue (MALT)?
Adenoids and tonsils
Where do T lymphocytes mature?
Thymus
Where does haematopoiesis and B cell maturation occur?
Bone marrow
What are a, B and y globulins?
Acute phase proteins
Innate humoral immunity
Eg complement (B), CRP, pro-calcitonin, mannose binding, antibodies (y)
What is the structure of an antibody?
Light chain - small
Heavy chain - big
Antigen binding site - variable
Y shaped
Which antibody is produced on first contact with antigen?
IgM
Which antibody does the major work and is present in later stages of infection?
IgG
What parts form physical barriers against infection?
Skin
Mucus
Respiratory cilia
Commensal organisms
Which parts form biochemical barriers against infection?
Sebaceous secretions in skin
Lysozyme in tears
Spermine in sperm
Gastric acidity
Which mucosal surfaces do most infections enter the body by?
Nasopharynx
Respiratory tract
Alimentary tract
Genito-urinary tract
What is a risk of intubation in an immuno compromised patient?
Ventilation associated pneumonia
What name is given to the process where microbes are recognised and engulfed which are then killed by the release of toxic chemicals into the enclosed vacuole?
Phagocytosis
What cell types are involved in phagocytosis?
Neutrophils
Macrophages and monocytes
What is neutropenia?
Abnormal low levels of neutrophils
Who might be susceptible to neutropenia?
Someone undergoing chemotherapy
What can a genetic inability to produce toxic chemicals within phagocytes cause?
Immunodeficiency - chronic granulomatous disease
Chadiak higashi syndrome
Describe the 7 stages of phagocytosis
Chemotaxis and adherence of microbe to phagocyte
Ingestion
Formation of phagosome
Fusion of phagosome with lysosome to form phagolysosome
Digestion by enzymes
Formation of residual body containing indigestible material
Discharge of waste material
What is an oxidative burst?
Rapid release of reactive oxygen species from phagocytes
What are natural killer cells?
Innate immune response
Lymphocytes that perform direct and antibody dependent cell toxicity
Which cells do not express MHC class 1?
Malignant or infected cells
What do natural killer cells detect, which activates them?
Lack of MHC class 1 at the cell surface
How do natural killer cells exert their cytotoxic effects?
Pore-forming molecules are inserted into target cell and cytotoxic chemicals are pumped in
In which diseases can NK cells be deficient?
Genetic diseases affecting T lymphocytes
X linked lymphoproliferative syndrome
What are acute phase proteins?
Innate humoral factors
Immediate and non specific cytotoxicity
C reactive protein, pro calcitonin, alkaline phosphatase, ferritin
What does CRP do?
Binds to surface molecules of bacteria and fungi
Inhibitory effects
Promotes complement binding
What are complement proteins and where are they made?
20 of them
B globulins
Produced by liver
Work in cascade
What 3 pathways can activate complement system?
Alternative - microbe activated
Classical - antibody activated
Lectin - mannose binding lectin activated
What does MHC stand for?
Major histocompatibility complex
Which cells express MHC class II?
Antigen presenting cells
Which cells will MHC class I be presented to?
Cytotoxic t lymphocytes
Which cells will MHC class II be presented to?
Helper T lymphocytes
What is important in organ transplantation?
MHC/HLA matching
What are the 2 antigen presenting cells?
Macrophages
B lymphocytes
What do T helper cells do?
Release cytokines to recruit more macrophages or antibody binding
What do cytotoxic T cells that have detected an antigen do?
Replicate and differentiate
Which cells are targeted by HIV?
CD4 - helper T cells
What ensures a specific response and memory of the immune system?
Clonal selection and expansion
What forms adaptive humoral immunity?
Antibodies
Which cells produce antibodies?
Plasma cells - differentiated B lymphocytes
What are 3 stimulating factors of the immune system?
Presence of antigen, helper T cells, cytokines
What are 3 inhibiting factors of the immune system?
Removal of antigen, suppressor T cells, cytokine breakdown
What improvements exist in the antibody response produced on second exposure to an antigen?
Less lag time
Larger peak response
Increase in IgG
Higher average affinity
Where does the development of central T Cell tolerance occur?
Thymus
Which cells produce interleukins?
MPS - macrophages and monocytes
Helper T cells
What do interleukins cause?
Proliferation
Differentiation
Activation
Chemotaxis
Which cells produce TNF?
MPS cells - macrophages and monocytes
What effects can TNF have?
Fever, inflammation, enhanced immunity, septic shock, anorexia, cachexia (muscle wasting)
Anti-TNF drugs are useful in treating autoimmune diseases, but what are their risks?
Cancer
Re activation of latent infections eg TB
Which cells produce interferons?
Virus infected cells
T helper cells
Which cells are activated by interferons?
NK cells and cytotoxic T cells
Macrophages and antigen presentation is upregulated
Interferon preparations can be used as medicines, what are their side effects?
Flu like symptoms
What does SIRS stand for?
Systemic inflammatory response syndrome
What is an infection?
Invasion and multiplication of pathogenic microbes
How is SIRS diagnosed?
> 1 of :
temperature 38°C
heart rate >90/min
respiratory rate >20/min or pCO2 12x10^9/dl or >10% immature WBCs
Why will elderly people likely develop a different response pattern with SIRS/sepsis?
Elderly people dont have muscle mass to develop fever and so will drop their temperature when they’re septic
What is sepsis?
Systemic inflammatory response to infection
SIRS + infection
What is severe sepsis?
Sepsis + organ dysfunction
Includes septic shock
What is septic shock?
Sepsis + hypotension (SBP <90mmHg) despite fluid
resuscitation + perfusion abnormalities eg. lactic acidosis, decreased urine output, decreased Glasgow coma scale score
What can cause SIRS?
Pancreatitis
Burns
Trauma
What is the main cause of sepsis?
Bacterial infection
Give 6 infections which can potentially cause severe sepsis
Meningitis Pneumonia Infective endocarditis Bacterial gastroenteritis Pyelonephritis Cellulitis Osteomyelitis Malaria
What is the sepsis 6?
Within 1 hour of suspecting severe sepsis:
- Give high flow oxygen
- Take blood cultures
- Give empirical IV antibiotics
- Measure FBC and serum lactate
- Start IV fluid resuscitation
- Start urine output measurements
What does plasma consist of?
Water
Organic compounds and electrolytes
Plasma proteins - albumin, globulins, fibrinogen
What is haematopoiesis?
Production of mature blood cells - White, red, platelets
Where does haematopoiesis occur?
Yolk sac
Liver and spleen
Red marrow
What are the precursor cells of platelets?
Megakaryocytes
Describe the cell lineage of T and B cells maturation
Pluripotent stem cells –> lymphoid multipotent progenitor cells –> t and b stem cells
Describe the cell lineage of GEMM (granulocyte, erythrocyte, monocyte, megakaryocyte) cell maturation
Pluripotent stem cells --> multipotent progenitor cells --> Erythrocyte committed cells Basophil committed cells Megakaryocyte committed cells Eosinophil committed cells Granulocyte/monocyte committed cells
What is the process of production of non lymph blood cells called?
Myelopoiesis
Which growth factors influence haematopoiesis?
Paracrine - G- CSF (colony stimulating factor)
Endocrine - EPO from kidney
What three aspects of haematopoiesis are controllable?
Proliferation
Differentiation
Maturation
What growth factor could be given to combat neutropenia?
Colony stimulating factor to stimulate cell division in bone marrow
Why is the lifespan of erythrocytes important in monitoring diabetes?
Erythrocytes - 4 months
Glycosylated haemoglobin - HbA1c test shows glucose control over the lifespan of these cells. Prolonged time period
Which blood cells have the shortest life span?
Basophils
What is the process of erythropoiesis under control by at all stages?
Erythropoietin EPO
What affect does EPO have on erythropoiesis?
Increases rate of mitosis
Decreases maturation time
What 4 things does erythropoiesis require?
EPO
Iron
Folic acid
Vitamin B12
How long do RBC precursors spend developing in the bone marrow?
7 days
At what point during erythrocyte maturation do the cells stop undergoing mitosis?
Once they become late erythroblasts (orthochromatic)
At which point during erythrocyte maturation is iron required?
Early on as it is required for Hb production
What does maturation of erythrocytes involve?
Decrease in cell size Hb production Loss of organelles Acquisition of eosinophilic cytoplasm Extrusion of nucleus Acquisition of bi concave disc shape (cytoskeleton)
What advantages does the biconcave shape of erythrocytes provide?
Large surface area
Minimise diffusion distance
Increase flexibility
Minimise tension with cell swelling
What name is given to increased levels of erythropoiesis?
Polycythaemia
What term describes an anaemia where the erythrocytes are pale?
Hypochromic anaemia
What proteins form the RBC cytoskeleton?
Ankyrin, spectrin alpha and beta, actin
What happens to RBC in which the cytoskeleton doesn’t form properly and the cells become spherocytes?
Splenic macrophages haemolyse them
Give an example of a disease caused by miscoding of Hb
Sickle cell anaemia
How is iron transported in the blood?
Bound to transferrin
How does iron get from food to marrow?
Taken up from gut by heme transporter if heme iron
Taken up from gut by DMT1 if Fe2+
Can be stored as ferritin or transported into blood by ferroportin1
Travels in blood to the red marrow
What is the normal range of iron levels?
35-90 mmol
What are 3 causes of iron deficiency?
Increased demand
Inadequate absorption - Crohns, coeliac
Blood loss - external (internal bleeding, iron can be recycled)
Describe how iron deficiency anaemia can develop
Net loss of iron, exhaustion of store Decreased serum iron Compensatory increase in iron binding capacity Reduced transferrin saturation Reduced delivery to bone marrow
What type of anaemia will vitamin B12 deficiency result in?
Macrocytic, normochromic anaemia
What is required for vitamin B12 absorption?
Intrinsic factor
Where is folic acid absorbed?
Duodenum and jejunum
What is the main cause of vitamin B12 deficiency?
Malabsorption
What can cause folic acid deficiency?
Reduced intake
Malabsorption
Drugs - alcohol, anticonvulsants
Increased demand - high cell turnover eg cancer
What can cause marrow aplasia?
Environmental insult can cause stem cells to express new antigens or have reduced proliferative and differentiative capability
Chemotherapy
Autoimmune disorders
What is aplastic anaemia?
Loss of trilineage haematopoiesis - pancytopaenia
Loss of ability of stem cells to generate mature blood cells
What can cause leukopenia?
Suppression of haematopoietic stem cells
Suppression of committed granulocytic precursors
Ineffective haematopoiesis
Increased peripheral utilisation
What can cause leukocytosis?
Increased production in marrow
Increased release from marrow stores
Decreased margination
Decreased extravasation into tissues
What can cause increased production of leukocytes from the marrow?
Chronic infection or inflammation
Paraneoplastic - Hodgkin lymphoma
Myeloproliferative disorders - eg chronic myeloid leukemia
What can cause Neutrophilic leukocytosis?
Acute bacterial infections
Sterile inflammation eg tissue necrosis from myocardial infarction, burns
What can cause eosinophilic leukocytosis (eosinophilia)?
Allergic disorders - asthma, hay fever
Skin diseases - pemphigus, dermatitis herpetiformis
Parasitic infestations
Drug reactions
Malignancies - Hodgkin and some non-Hodgkin lymphomas
Collagen vascular disorders
Atheroembolic disease
What can cause basophilic leukocytosis (basophilia)?
Rare, indicative of a myeloproliferative disease - chronic myeloid leukemia
What can cause monocytosis?
Chronic infections - tuberculosis, bacterial endocarditis, rickettsiosis, and malaria
Collagen vascular diseases -systemic lupus erythematosus Inflammatory bowel diseases - ulcerative colitis
What can cause lymphocytosis?
Accompanies monocytosis in many disorders associated with chronic immunological stimulation - tuberculosis, brucellosis
Viral infections - hepatitis A, cytomegalovirus, Epstein-Barr virus
Bordetella pertussis infection
Which immune cells are likely involved in allergy, parasitic infections, infections by multicellular organisms?
Basophils and eosinophils
How do dendritic cells work?
Engulf microbe then travel to lymph nodes where they present to cytotoxic T cells
What is hypersensitivity?
Inappropriate and excessive immunological reaction to an antigen
Can be allergy and or anaphylaxis
What is an allergen?
Antigen that induces a hypersensitivity reaction
What is a type 1 hypersensitivity reaction?
IgE and mast cell mediated Allergy Asthma Anaphylaxis Atopy
What is a type 2 hypersensitivity reaction?
Antibody dependent - IgM, IgG Autoimmune haemolytic anaemia Goodpastures syndrome Myasthenia gravis Graves' disease
What is a type 3 hypersensitivity reaction?
Immune complex mediated
Serum sickness
Rheumatoid arthritis
Systemic lupus
What is a type 4 hypersensitivity reaction?
Delayed or cell mediated - t lymphocytes Allergic contact dermatitis Chronic transplant rejection Multiple sclerosis Tuberculin skin test
What is atopy?
Pre disposition to allergy
Often familial or genetic
Describe the process of a type 1 hypersensitivity reaction?
On first exposure to allergen, T helper cells are activated and via IL4, stimulate B cells to undergo class to produce IgE antibodies
IgE binds to mast cells to sensitise them
Second exposure to antibody, cross linking of IgE, activation of mast cell to release mediators - de granulation
Vaso active amines and lipid mediators cause immediate reaction - vasodilation, smooth muscle contraction, tissue damage
Late reaction caused by cytokines - inflammation, lymphocyte recruitment
What symptoms may be seen in airway and eye mucous membrane from a type 1 hypersensitivity reaction?
Pruritus, sneezing, rhinorrhoea, lacrimation
What reaction may be seen in the skin from type 1 and 4 hypersensitivity reactions?
Pruritus and urticaria - histamine reaction
What reaction may be seen in oral and intestinal mucous membranes due to a type 1 hypersensitivity reaction?
Pruritus and angioedema
What symptoms might be seen in anaphylaxis?
Local swelling Flushed Faint Dyspnoea Peri oral paraesthesia Throat and chest tightness Wheeze Pale Sweaty Hypotensive collapse Unconscious Death
What blood measures can be taken to prove a type 1 hypersensitivity response?
Eosinophil count
Tryptase
IgE
What is skin patch testing used for?
Allows identification of exact allergen causing a reaction
What would a positive skin patch test show?
A lesion >3mm larger than the negative control
How does de sensitisation therapy against allergens work?
Creates tolerance to allergen by exposure to gradually increasing doses delivered sublingually or sub cut
Small risk of anaphylaxis
Requires weekly/monthly treatment for 3 years
What is the treatment strategy for anaphylaxis?
ABC Lie patient down High flow oxygen IV fluids Adrenaline 500mcg IM (1:1000, 0.5ml of 1mg/mL) IV chloamphenamine IV hydrocortisone Nebulised salbutamol Repeat Adrenaline after 5 mins if no improvement
What layers make up a blood vessel wall?
Intima - endothelium, basement membrane, connective tissue, internal elastic lamina
Media - circumferentially arranged smooth muscle
Adventitia - connective tissue contains neurovascular supply
What factors determine fluid transit across the capillary walls?
Plasma hydrostatic and oncotic pressure
Interstitial hydrostatic and oncotic pressure
What 5 things can cause oedema?
Increased hydrostatic pressure Reduced plasma oncotic pressure Lymphatic obstruction Sodium retention Inflammation
What disorders can result in oedema?
Heart failure Renal failure Malnutrition Decreased liver function Nephrotic syndrome
How does heart failure result in an increase in blood volume?
Decreased renal blood flow
Activation of RAAS
Na and water retention
Increased blood volume
What factors affect the clinical consequence of oedema?
Volume
Site
Underlying cause
Risk of infection in involved tissues
What causes nutmeg liver to be seen histologically?
Right sided heart failure
Central veins of liver have increased hydrostatic pressure, leads to cell death
What is haemorrhage?
Extravasation of blood into extravascular space
What are the 5 patterns of haemorrhage?
Haematoma Petechiae Purpura Ecchymoses Haemorrhage into body cavity
What factors affect the significance of haemorrhage?
Volume of blood lost
Rate of blood lost
Medical fitness pre blood loss
Site of bleeding
What is the pathological counterpart of haemostasis?
Thrombosis
What are the 3 key components of haemostasis and thrombosis?
Vascular wall
Platelets
Coagulation cascade
What is the sequence of normal haemostasis?
Endothelin release from damaged vessel causes vasoconstriction
Presence of collagen causes platelet adhesion as von willebrand factor binds to collagen
Platelets change shape and release granules including thromboxane A2 which recruits more platelets which aggregate to form platelet plug and ADP which activates a complex on platelets and allows them to bind fibrinogen
Tissue factor released from endothelium causes phospholipid expression on platelets which in turn leads to thrombin activation and fibrin polymerisation
Thrombomodulin and I-PA are released which start the anti-thrombotic events
What factors normally contribute to making the endothelium anti - thrombotic?
Anti platelet - thrombin binding to receptor causes prostaglandin, NO and adenosine diphosphatase release from endothelium to inhibit platelet aggregation
Anti coagulant - thrombin binding to thrombomodulin causes activation of protein C which causes proteolysis of factor Va and VIIIa. Tissue factor pathway inhibition inactivates factor VIIa complexes. Anti thrombin III binds to heparin like molecule, this complex inactivates thrombin and factors Xa and IXa
Fibrinolysis - tPA from endothelium initiates fibrinolytic cascade
What are the 2 key functions of platelets?
Form haemostatic plug
Provide surface for recruitment and concentration of coagulation factors
How does aspirin prevent platelet aggregation?
COX inhibitor - inhibits synthesis of thromboxane A2 which normally stimulates recruitment of further platelets
How does clopidogrel inhibit platelet aggregation?
Irreversibly inhibits P2Y12 receptor which is an ADP chemoreceptor on platelets
This means that new platelets cannot detect the aggregation signal (ADP) released from granules of the primary platelets
How does Abciximab inhibit platelet aggregation?
Blocks GP IIb/IIIa receptor which prevents fibrinogen complexing and therefore no further platelets can aggregate
What is the goal and end point of the coagulation cascade?
Produce thrombin and produce secondary haemostatic plug
What extra factors do some steps of coagulation cascade require?
Ionised calcium
Phospholipid surfaces
Describe some of the key steps of the coagulation cascade
Tissue factor released from damaged endothelium activates factor VII which in turn activates factor VIX. This activates factor Xa which activates thrombin from prothrombin
Thrombin activates fibrinogen to fibrin clot
What factors does warfarin prevent activation of?
Prothrombin and factor VII by inhibition of vitamin K epoxide reductase
How does heparin work?
Activates anti thrombin III which inactivates thrombin and clotting factors
What is dabigatran?
Reversible inhibitor of thrombin
Effects measured by thrombin clotting time
Why is heparin faster acting than warfarin?
Inactivates factors that are already present
Warfarin prevents formation of new factors but not the ones that are already there so they have to be used up first
What are D Dimers?
Fibrin degradation products
Blood test to look at clot break down
What is plasminogen?
Precursor to plasmin which degrades fibrin
What is streptokinase?
Clot busting drug
Binds to plasminogen to make it functionally act like plasmin
Short half life
Degrades both fibrin and fibrinogen
Antigenic and can cause severe allergic reactions
What are alteplase, reteplase and urokinase?
Recombinant tissue plasminogen activators
Give an example of a bleeding disorder due to disorder of vessels
Hereditary haemorrhagic telangiectasia - leaky blood vessels
Give an example of a bleeding disorder due to platelet disorder
Von willebrands disease
Give an example of bleeding disorders caused by coagulation disorder
Haemophilia A (factor VIII) and B (factor IX, Christmas)
What is Virchows triad?
Describes 3 main factors that predispose to thrombosis
Hypercoagulable state, circulatory stasis, endothelial injury
What is heparin induced thrombocytopenia?
Development of low platelet count due to administration of heparin
Predispose to thrombus formation
What is antiphospholipid syndrome?
Autoimmune disorder characterised by arterial and venous thrombosis
Hypercoagulability
What is the fate of thrombi?
Propagation - move towards heart if in venous system
Embolisation - break off and move to distal site
Dissolution - fibrinolysis breaks down clot
Organisation - damaged tissue, scar, new blood vessels can form through clot
What can be the clinical consequences of a thrombus?
Cause obstruction to blood flow - oedema and congestion
Embolism and cause infarction in distal tissue
What can be the clinical effects of an arterial thrombus?
Usually due to rupture of atheroma
Ischaemic necrosis (infarct) in tissue
Source of emboli
Can cause MI and stroke
What are clinical consequences of a venous thrombosis?
Local effects of DVT
50% silent, swelling, pain, tenderness, discolouration, increased temperature
What is disseminated intravascular coagulation?
Sudden or insidious onset of widespread fibrin thrombi in the microcirculation which can cause multi organ failure and consumptive coagulopathy and bleeding (clotting and bleeding at same time)
Risk of occurrence whenever there is widespread thrombin activation
What can be the outcomes from a pulmonary thromboembolism?
Occlusion of medium or small pulmonary artery with or without infarct of lung
Massive embolism : saddle emboli which occludes main pulmonary arteries - sudden death
Multiple emboli may lead to pulmonary hypertension
What are signs and symptoms of a PE?
Chest pain SOB Collapse Cough Haemoptysis Tachycardia Hypotension Tachypnoea Elevated JVP
What clinical consequences can an arterial thrombus cause?
Left side of heart eg ventricular thrombus in MI, atrial fibrillation, infected heart valve
Large artery, usually atheromatous - aneurysm of aorta
Effects include infarcts of organs e.g stroke, gangrene of limb
What treatments are given for arterial thrombus?
Prophylaxis - aspirin, clopidogrel
Treatment - streptokinase, tPA
When is the 1 occasion when a venous thrombus could enter the arterial circulation?
Via patent foramen ovale or septal defect
Other than a thrombus, what things can cause emboli?
Atheroma Air Amniotic fluid Nitrogen Tumour cells Fat Foreign material
What are the stages of athersclerotic plaque formation?
Fatty streak formation: Endothelial damage, Uptake of modified LDLs, Adhesion/infiltration of macrophages, foam cells when ingest LDL
Smooth muscle proliferation in intima, collagen deposition
Fibrous cap formation
What modifiable factors can increase risk of formation of an atherosclerotic plaque?
Shear stress at artery branch points, increased in hypertension
Toxic damage by chemical exposure, eg cigarette smoke (oxidise LDL)
High lipid levels in FH, DM and high fat diets (glycate LDL)
Viral or bacterial infection
What is claudication?
Reduced blood flow to the limb which causes cramp
How can an atherosclerotic plaque lead to thrombus formation?
Collagen cap of plaque is fragile
Calcification of cap increases fragility further
Rupture of cap exposes blood to collagen which triggers thrombus formation
What are some non modifiable risk factors for atherosclerotic plaque formation?
Age
Male, women after menopause
Family history of CHD or FH
How do catecholamines cause vasoconstriction?
Bind to alpha receptors which are GPCRs bound to Gq
This activates phospholipase C which generates IP3 and DAG
This causes Ca release from stores which leads to opening of Ca activated Cl channels
Depolarisation causes voltage gated Ca channels to open
Ca binds to calmodulin which activates myosin light chain kinase
This phosphorylates myosin heads which form cross bridges and contraction occurs
Which Ca channel blockers are cardio selective, vascular selective and intermediate?
Verapamil is cardio selective
Nifedipine is vascular selective
Diltiazem is intermediate
How do catecholamines cause vasodilation?
Act on B receptors to activate Gs which causes increase in cAMP
This activates protein kinase A which activates Ca ATPase to pump Ca into sarcoplasmic reticulum, PKA phosphorylates K channels so causes hyperpolarisation, PKA phosphorylates myosin light chain kinase to inactivate it
How does NO cause vasodilation? And where is it made?
Synthesised by endothelial cells by nitric oxide synthase, stimulated by increased Ca in endothelial cell (shear stress can cause this)
NO diffuses across membrane into tunica media to activate guanylate cyclase
This increases levels of cGMP which activates protein kinase G which stimulates Ca ATPase and K channels, and inactivates MLCK
What is a Myogenic response?
An increase in arterial blood pressure will be compensated for locally by vasoconstriction of vascular beds to increase resistance and reduce blood flow in order to maintain a relatively constant perfusion to organs
Mechanosensitive ion channels detect stretch and depolarise so increasing Ca influx
What is haemoglobin?
Binds oxygen at 4 sites to transport it around body
Tetrameric protein
2 alpha and 2 beta subunits
Each subunit has haem and globin groups