TOPIC 8 - blood bois Flashcards
what is blood?
- viscous fluid pumped by heart and vascular system
what does blood contain?
RBC
WBC (immunoglogy)
platelets (clotting)
contains plasma
volume of blood?
5 liters
function of blood
- hydration of tissues
- delivery of oxygen and nutrients
- delivery of endocrine hormones
- regulate body temp+pH
- fight infection -immune response initiation
- prevent own blood loss through blood clotting
erythrocytes background check
- most abundant blood cell
- for oxygen transport mainly - Fe v important in this
- no nucleas/anucleate
- no mitochondria= all energy from glucose in glycolytic pathway
- contain haemoglobin = regulates O2 transport
- also delivery= glucose, AA, fatty acids, vitamins, minerals
- collect waste products from tissues to drop off at organs: kidneys and liver
examples of endocrine hormones
- insulin - B cells in pancreas
- Oestrogen, progesterone, testosterone- overs/testies
- vasopressin - prosternar pituatary lobe
- Adrenalin - adrenal medulla
regulating body temp
- absorb heat via vasodilation and constriction
regulating body pH
- maintenance of fluid volume ions and proteins to prevent fluid loss of our blood into inerstitial spaces
- maintenance pH proteins act as buffers to prevent changes in pH
how do we Prevent blood loss- Haemostasis
- platelets: small and anucleate = clump together
- Blood coagulation;ation pathway: through formation of thrombin clot
common progenitor cell of all blood cells?
multi potential haematopoietic stem cell
made in bone marrow
2 major lineages from the multi potential haematopoeitic stem cell?
myeloid
lymphoid
both in bone marrow
lineage of myeloid (4 cells) and where formed
megakaryocyte (bone marrow)
erythrocyte (blood/lymph)
mast cell (tissue)
myeloblast (bone marrow)
lineage of myeloblast?
basophil neutrophil eosinophil monocyte all in blood/lymph
lineage of monocyte?
macrophage - in tissue
lineage of lymphoid
natural killer cell- eg. large granular lymphocyte
small lymphocyte
all in blood and lymph
lineage of small lymphocyte
T cells
B cells – turn to plasma cells
in blood/plasma
how does blood coagulation work?
platelets = activated on exposure of injury blood coagulation fibrin forms mesh work traps other cells forms haemopoatic plug blood cant escape
what test is used for diagnosis of haemotogical diseases ?
peripheral blood smears
using blood plasma as diagnostic
- put in tube with anticoagulant = prevent clotting
blood plasma contains blood coagulation and immune system factors
most abundant blood plasma proteins?
- albumin
- immunoglobulins (for infection)
- fibrinogen (for clotting)
what is the significance of hematocrit?
important component made by RBCs
marker of blood tea;th
changes in this = indicator of disease
using blood serum as diagnostic
allowed to clot before centrifuged
has no clotting factors
how are blood groups classified?
based on antigens of RBC membrane
what does mixing of incompatible blood groups lead to?
endogenous antibodies (self antibodies) react with antigens on RBC membrane
get cross reaction in RBC
RBC carrying a foreign antigen = immune response
= aggregation
=blood vessles blocked
= eventually RBC lysis
what are agglutinogens?
antigens
what are agglutinins
antibodies in plasma
blood group A features?
A antigens on RBC
anti B antibodies in plasma
blood group B features?
B antigens on RBC
anti A antibodies in plasma
blood group O?
no antigens
anti A and anti B antibodies in plsma
universal donor
blood group AB
both A and B antigens
no antibodies
universal receptor
agglutinins function
bind to agglutinogens
not carried by RBC
cause agglutination
what is acute haemolytic reaction
happens when RBC lysis
due to incompatable blood groups mixing
symptoms of acute hemolytic reaction
systemic: chills, fever
vascualr: hypotension, uncontrolable breating
heart: increased heart rate
chest: contracting pain
lumbar region: pain
kidney fialure
bleeding
what are rhesus (Rh) blood groups?
based on ion channel antigen on RBC memrbane
Rh+ = common = A+ (has Rh antigen on surface)
Rh- = rare = A- (No Rh antigen on surface)
mixing of two= just don’t do it
Rh- mixing with Rh+
RBCs contain no Rh agglutinogens
agglutinins against Rh+ RBCsb produced
how does haemolytic syndrome in the foetus occur?
in 1st pregnancy:
- mother protected by the placenta-blood barrier = not exposed to Rh agglutinogens until time childbirth due to placental tearing
- anti-Rh agglutinins generate and antibodies circulate
- in 2nd preganacy: antibodies cross placental barrier- born with severe anemia
what are the three phases to the circulatory haemostatic process?
hemorrhage - bleeding
thrombosis - clotting
fibrinolysis - clot dissolution
what systems interact for haemostasis?
- blood vessels
- platlets
- coagulation system
- fibrinolytic system
- inhibitors of the above
what is a vascular spasm?
at the site of injury the blood vessel constricts to reduce blood flow and therefore blood loss
what is the primary response?
platelet, endothelial and fibrinogen mediated
- temporary platelet plug forms to prevent blood loss
outline the key steps of the primary response
A primary plug forms to stop blood loss
- adhesion - platelets stick to exposed collagen at injury site and change shape
- secretion - granules containing proteins and factors released, attracting more platelets to the site
- aggregation - platelets stick together with fibrinogen
- activation of coagulation cascade to consolidate the plug
what is the lifespan of a platelet?
7-10 days
how are platelets kept in the unactivated state?
endothelial cells release chemicals which keeps them in their resting disc shape
outline the 4 phases of platelet shape change
- flowing disc shape
- when collagen exposed, it touches the surface and slows down, begins rolling - rolling ball shaped
- arms begin to stick out, this allows it to grab onto other platelets and slow down (allows them to aggregate) - hemisphere shaped
- firm but reversible adhesion - first stage of platelet plug - spreading platelet
- irreversible adhesion
what are the two types of granules in platelets, and what are their roles?
dense granules
- ATP, ADP, serotonin, Ca2+
- help platelet activation through positive feedback (attracts more platelets to the area)
alpha granules
- factor IV/4, plasminogen activator inhibitor/PAI-1, growth factor, chemokines, platelet derived growth factor
- help coagulation and aid wound healing
overall both amplify haemostaic response
what is the fibrinogen receptor on an activated platelet?
⍺IIbß3 - allows activated platelets to aggregate, using fibrinogen as a ‘glue’
when platelet unactivated A11bB3 unable to bind to fibrinigin
what is the collagen receptor on platelets?
⍺2ß1
how is potential infection at a injury site prevented?
platelets also release chemicals that attract leucocytes, the platelets then grab onto the leucocytes and hold them in place
what triggers the coagulation cascade?
tissue factor is released into the blood stream from damaged cells
noramally TF on inside of cell but when cell damaged TF on outside
what does tissue factor activate?
factor VII → factor VIIa
what does factor VIIa activate?
factor X → factor Xa
what does factor Xa activate?
prothrombin → thrombin
NB- all of this activation on activated platelet surface
what does thrombin activate?
fibrinogen → fibrin
thrombin produced close proximity to fibrinogen = produces fibrin rapidly
what role does thrombin have in activation?
it feeds back and keeps promoting activation of factors and therefore its own production - massive amplification
why is vitamin K necessary for clotting?
needed so that clotting factors can bind to platelet surface via Ca2+
BLOOD DISEASES
WELCOME XOXO
what are the 4 main disorders of blood?
bleeding
thrombosis
hereditary angioedema
complement deficiency
what are 7 the main diseases of blood cells?
haematological malignancies sickle cell anaemia thalassaemia leukopenia thrombocytopenia infectious mononucleosis haemoglobinopathies
definition of blood diseases?
affect the quantity and/or function of cells in the blood or proteins in the blood clotting or immune systems
anaemia?
decreased no. RBC
leukopenia?
decreased no. WBC
thrombocytopenia?
decreased no. platlets
erythrocytosis?
increased no. RBC
leukocytosis?
increased no WBC
thrombocythemia/thrombocytosis?
increased no. platletes
what certain factors will cause severe blood loss?
injury (acute) disease (chronic) thrombocytopenia coagulation deficiencies ( haemophilia) vitamin K deficiency drugs liver disease infection/sepsis aneurysm rupture
major causes of thrombosis?
atheroscelosis cancer immobilisation surgery hypercoagulability thrombosythaemia
can retroviruses cause cancer of blood cells?
yes - eg. T-lymphotropic virus (HTLV-1)
associated with leukaemiia
whats Burkitt’s lymphoma
diseases caused by translocation between c-MYC gene on chromosome 8 with IgH loci on chromosome 4
polycythaemia?
increased no of RBC
thrombocythaemia?
increased no. platletes
myelofibrosis?
increased no. megakaryocyte
what are myeloid malignancies?
heterozygous disorders
uncontrolled proliferation
and/or blockage of differentiation abnormal myeloid progenitor cells
what is chronic myeloid leukaemia?
’ the philadelphia chromosome’
translocation between 22 and 9
= leads consecutively active tyrosine kinase
= uncontrolled cell proliferation
what is leukaemia?
accumulation WBC in bone marrow
what does leukaemia do?
lead bone marrow failure
- decreased RBC
- decreased platelets
- increased WBC in blood
- but soon after decreased WBC due to bone a=marrow failure
symptoms of leukaemia
- blood hyper-viscosity due increased WBC = causes respiratory / neurological disorders
- tiredness
- anemia
- bleeding
what is lymphoma
affects lymph nodes
T/B lymphocyte neoplasia
eg. non-hodgkin or hodgkin
characterised: Reed Sternberg cells
what are Reed-Sternberg cells
originate from B lymphocytes
become enlarged are multinucleate
or bilobed nucleus
what are the symptoms of anaemia?
tiredness pallor fainting tachycardia shortness of breath
what is anaemia caused by?
abnormal RBC production/destruction
what does anaemia do?
leads to tissue anoxia reduction in O2 delivery to tissues sends message to kidney (major source of erthoportin) kidney stimulates RBC production negative feedback loop
NB-often ppl w/ kidney disease have anaemia
forms of anemia
mild= thallassemia and sickle cell anaemia severe= lethal
what is erythropoietin
drives RBC production
role of erythropoietin: steps in process of rbc production
- anaemia hypoxia
- leads to tissue hypoxia
- sends message to kidney
- kidney releases erythropoietin
- erythropoietin sent bone marrow
- leads to erythropoiesis
- leads to increased RBC mass
what is acute anaemia?
loss of large amount of blood
what is chronic anaemia?
blood loss when volume of blood lost exceeds the capability for haematopoiesis of bone marrow
example of chronic anaemia
bleeding peptide ulcer
what is haemolytic anaemia?
increased RBC destruction
- lifespan from 120 to 20 days
- bone marrow unable replace sufficient RBC
what are the two ways we can get haemolytic anaemia?
1) acquired - malaria/sepsis/drug induced
2) inherited - G6P dehydrogenase, Autoimmune Hemolytic Anemia
different ways we get acquired anaemia
- drug induced
- snake venom
- mechanical (heart valves)
- infections (malaria)
different inherited haemolytic anaemias
1) RBC cytoskeletal defects: mutation in a or b spectrin
2) RBC enzyme defects - G6PD deficiency
why is iron essential in blood?
essential element of haem group in Hb
iron deficiency = most common cause anaemia
causes of anaemia - iron deffiency
- diet induced
- blood loss
- infection
- growth spurts
- pregnancy
how does low iron lead to anaemia?
leads to microcytic anaemia= pale and small RBCs due to reduced Hb production = hypochromic
what is hypochromic?
less Hb in each RBC
what is megaloblastic anaemia?
Vitamin B12 or folate deficiency
pathophysiology of megaloblastic anaemia
- vit B12 and folate involved in DNA replication
- deficiency causes problems w/ mitosis or proerythroblast
- causes megaloblastic or macrocytic anaemia (large RBCs)
what is B12 deficiency caused by?
reduced absorption
what is folate deficiency caused by?
poor nutrition
alcoholism
malabsorption
certain drugs
cause of sickle cell anaemia
- mutation in HbB globin gene
- changes AA glu 6 to Val
- polymerisation of Hb - distorting RBC
effect of sickle cell anaemia
- “sickling of RBC”
- sickle cell crisis due to blockage of microvasculature
- heterozygosity confers protection against malaria
what is Thalassemia
- microcytic anemia
- defects in alpha or beta chains of Hb
- leads to ineffective erthropoiesis or hemolysis
factors that decrease effectiveness of erythropoietin
- iron deficiency
- vit B12 deficiency
- folate deficiency
- anaemia or chronic disease
do we have other reactions which generate thrombin ?
Factor 7a also activates factor 9 which generates factor 10a
what is the 3 parts to the haemostatic reponse?
1- plug hole where damage is (platelets interacting w/ vessel wall) - not v stable
2- consolidate plug: coagulation cascade
3- dissolve plug after healing
why must haemostatic response be localised?
so we get physiological and not pathological response
which haemostatic response results in immediate bleeding?
1' response as it is: - platelet mediated - endothelial mediated - fibrinogen mediated
which haemostaic response results in delayed bleeding?
2’ response - as plug not coagulated
- circulating enzymes
- platelet mediated
- fibrin- mediated
what does fibrin ensure?
forms meshwork that hold platelets together so makes sure plug is stable and not washed away
NB- if plug washed away/ not stable = embolisms
what is a quiescent state of a platelet
the resting state
before encounter injury
endothelial release chemical in blood to keep them in this phase
how to platelets respond to injury so rapidly?
undergo ‘explosive’ activation
- large no. receptors: interact w/ other cells and each other
- high no platelets: mass action effect
- rich signalling proteins
- positive feedback
what is the role of stimulatory agonist
activation of platelets - at site of injury to outweigh inhibitory agonists
what is the role of inhibitory agonists
- away from site of injury
- ensure we don’t get activation of platelets where we don’t need it
- helps it stay localised
BLEEDING
WELCOMIN
What are the 2 types of bleeding?
1- induced/acquired: trauma, surgery, infection
2- inherited- linked to coagulopathy disorder
what can be the causes of an external bleed?
trauma
surgery
what can be the causes of an internal bleed?
haemophillia
aneurysm rupture
drug induced
gastro intestinal
what are some bleeding triggers
trauma surgery sepsis aneurysm rupture drugs (anticoagulants, aspirin) vit K deficiency
what happens in DIC- disseminated intravascular coagulation
step 1- infection
step 2- sepsis- systemic infection
3- intravascular TF exposure (TF usually inside cells)
4a- systemic coagulation activation leads to microvascular clots - using up clotting factors faster than making them
4b- consumption of clotting factors and platelets in excess leads to bleeding -as liver can’t produce clotting factors fast enough and bone marrow megakaryocytes can’t release platelets fast enough
(4a and 4b happen simultaneously both lead to):
multiple organ failure
what is bleeding a consequence of in DIC
a systemic infection
what happens in AAA- abdominal aortic aneurysm
- progressive dilation of abdominal aorta
- high risk of rupture if aneurysm too large
- rupture- major bleeding - 50% deaths
why is vit K importnant?
-required for processing of factors 2,7,9,10
and proteins C and S
-vit K = cofactor for enzyme in this reaction
how does vit K work processing these factors?
1-precursor forms of factors 2,7,9,10 and proteins C and S undergo reaction with carboxyglutamic acid
2-enzyme catalyses reaction
3-result in completed forms of above factors and proteins
what happens in vit K deficiency?
- ineffective coagualtion factors produced
- will effect bleeding consequences
- major impact on coagulation cascade
what is warfin and why is it used?
- anticoagulant
- used when overactive haemostaic response
- inhibits epoxide reductase = so coagulation cascade
consequences of vit K deficiency
- malnutrition
- fat malabsorption
- liver disease
- due to vit K antagonists- eg.warfarin
- can be reversed by administration of vit K = rapid production coagulation protein by liver
what is haemostasis thromcoytopenia/ thrombastenia?
loss / dysfunction of platlets
through what is thromcoytopenia/ thrombastenia acquired ?
Leukaemia Blood loss Disseminated intravascular coagulation (DIC) Drug-induced Immune thrombocytopenic purpura (ITP)
All lead to reduced platelet coats = high risk of bleeding
what are the 3 primary causes of inherited bleeding?
- Platelet dysfunction
- Coagulation factor deficiency or haemophilia (severe)
- Thrombocytopenia (mild)
what are the symptoms of a coagulation factor defect?
- large bruising
- slight bleeding from cuts
- bleeding day after surgery
what are the symptoms of platlets disorders?
- small bruising
- profuse bleeding from cuts
- common nosebleeds
- immediate bleeding after surgery
what happens in diseases Von Willebrand syndrome and Bernard-Soulier syndrome?
Defects in platelet-platelet interaction.
platelets bind to site of injury but platelets don’t stick together= no aggregation
what happens in diseases Glanzmann thrombasthenia.
and Congenital afibrinogenemia.
Defects in platelet granules, secretion and signal transduction.
so when platelets aggregate can’t consolidate themselves = no positive feedback
is haemophilia A or B an X-linked disorder?
both
NB- severity level is consistent between family members as same mutation is carried
what happens in haemophilia?
insufficient thrombin generation
=major effect on coagulation cascade
what are the sevrity levels in haemophillia?
-Normal (factor VIII or IX level = 50-150%)
-Mild hemophilia
(factor VIII or IX level = 6-50% )
-Moderate hemophilia
(factor VIII or IX level = 1-5%)
Severe hemophilia
(factor VIII or IX level = <1%)
what are the consequences of uncontrolled bleeds in haemophilia?
- bruising
- joint bleeding and destruction
after repeated joint bleeds= inflammation= stiff joint = lock joint syndrome
how can we find out if someone is missing a clotting factor in their blood?
- mix plasma of healthy person and diseased patient
- clotting time should be restored
- now we do genetic test
which pathway does the APTT- activated partial thromboplastin time test?
looks at factors in the intrinsic pathway
which pathway does PT - prothrombin time test?
factor 7
if clotting time is not corrected after mixing with normal plasma- what does this imply?
due to inhibitors- has induced autoimmune response
THROMBOTIC DISEASE
WELCOME X
what is thrombosis?
formation of a blood clot inside the vessel, blocking blood circulation
what are the consequences of thrombosis?
ischaemia (tissue death), malfunction, pain or swelling in the organ or tissue affected
what are the main thrombotic disorders of arterial thrombosis?
- Myocardial infarction (MI; heart)
- Atrial fibrillation (AF; heart)
- Peripheral vascular disease (PVD; leg)
- Stroke (brain)
what are the main thrombotic disorders of Venous thrombosis?
- Deep vein thrombosis (DVT; arm/leg)
- Pulmonary embolism (PE; lungs)
what 3 things were included in virchow’s triad?
- stasis
- vessel wall injury
- hypercoagulability
what happens in the arterial thrombosis disorders?
-rupture of the atherosclerotic plaque= uncontrolled platelet activation
what is an atherosclerotic plaque?
deposition of lipids in from LDL in blood vessel wall: inflammation of the vessel wall with infiltration of macrophages (> foam cells) and fat deposits >
is the thrombus of the venous or arterial thrombosis platelet rich?
- thrombus of the arterial thrombosis is platelet rich
- that of the venous is RBC and fibrin rich
risk factors of arterial thrombosis?
- Advanced age
- Smoking
- Diabetes
- Hypertension
- Cholesterol
- Poor diet
- Lack of exercise
- Ethnicity
what are the 3 main phases of arterial thrombosis thrombotic response?
- Plaque fissure or rupture
- Adhesion and activation of platelets
- Activation of coagulation cascade
how does the plaque rupture in arterial thrombosis?
- lipids accumulate + become cytotoxic and oxidised
- change function of cells on top plaque
- plaque= unstable = cracks open= thrombus
which blood vessels are affected in arterial thrombosis?
those supplying heart tissue
Myocardial tissues= starved of oxygen = physical damage = cardiac arrest
what are the 2 types of arterial thrombi?
- mural thrombi
- occlusive thrombi
NB both due to controlled platelet division
what are the main features of mural thrombi?
- not occlude vessel
- unstable angina
- transient ischaemic attack
what are the main features of occlusive thrombi?
- occludes vessel
- myocardial infarction
- cerebral infarction
arterial thrombosis thrombotic response?
- platelets bind collagen and exposed to oxidised lipids from plaques
- activation platelets
- release of ADP and TxA2
- expansion thrombus
- reduced availability of endothelial NO and PGI2
- occlusive thrombi
name the 3 factors that drive expansion of thrombus in arterial thrombosis
- ADP (released on dense granuals)
- TxA2 (from arachidonic acid)
- thrombin ( coagualtion cascade)
NB- there action promoted by oxidised lipids - they reduce actions of inhibitors- NO and PGI2
how do we treat atherothrombosis?
Antiplatelets:
–Aspirin - inhibits what drives platelet activation
–Anti aIIbb3 -receptor for fibrinogen and vWF
- Abciximab, Tirofiban
–Anti P2Y
-Clopidogrel, Ticagrelor, Prasugrel
–Fibrinolytics = v.potent = high risk bleeding associated
what is DVT and its features?
deep vien thrombosis - in area of low blood flow= accumulation of cells- RBC = inflammation -platelet activation -fibrin generation clot = fibrin and RBC -less damage to blood vessel - blood clot can break = embolism
DVT symptoms
calf swelling
pain
associated odema
what is odema
leaky endothelial cells allows fluid accumulate in vasculature
press test to check for odema
RF of DVT
- immobilisation
- surgery
- cancer
- pregnancy
- contraceptives
- genetics
what is the most common embolism DVT causes
pulmonary embolism
- chest pain
- lungs stop functioning
- can be in both lungs
treatment for DVT
mmediate onset of anticoagulant effect:
–Unfractionated Heparin (intravenous – helps antithrombin to inhibit thrombin and Xa)
–Low Molecular Weight Heparin (LMWH; subcutaneous)
Slow onset:
–VKA, monitored by INR
what does the presence of D dimer in blood show?
ongoing thrombotic events
produced by breakdown of fibirin
what is circulatory stasis?
loss laminar flow and pooling around valves gaps between endo cells
what happens in endothelial dysfunction?
activation and exposure of TF after inflammation
what happens in hypercoaguable state?
localised inflammation
loss inhibitor function
too much activity of TM and protein C and S = thrombin accumulation
