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IIH > Week 1 > Flashcards

Week 1 Flashcards

1
Q

Monocytes

A

Innate immunity
Can migrate from blood into tissues and become macrophages
Key role is phagocytosis and cytokine production
- Engulf and destroy dead host cells and pathogens
-produce IL-12 and IFN gamma important for intracellular immunity

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2
Q

Granulocytes

A

Innate immunity
Neutrophils: live in blood for a few hrs then migrate into tissues where can live for 4-5 days, engulf and destroy bacteria- phagocytes
Granules contain lysosyme and myeloperoxidase- important for pathogen killing
Eosinophils - parasite infections (not phagocytic, release granules)
Eosinophils and basophils- allergy/atopy

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3
Q

Lymphocytes

A

Adaptive immunity
Small cells with low granularity (7-10um)
T cells: early progenitor from bone marrow but develops in thymus
B cells: develop in bone marrow (exit as naive cells, further differentiate in lymph nodes), produce antibodies
NK cells: develop in bone marrow

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4
Q

Platelets- clotting/haemostasis

A

Platelets have no nucleus but have granules which secrete substances which control clotting and breakdown of a blood clot
Key players in the process of haemostasis and the formation of blood clots (thrombosis) which work to prevent blood loss following injury. The clots are then cleared
Lifespan= 8-12 days then removed by macrophages in the spleen and liver
Low levels of platelets leads to easy bruising and haemorrhage

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5
Q

Red cells

A

Gas exchange
Biconcave bag of haemoglobin
Normoblasts extrude nucleus
Reticulocytes (young red cells)- no mitochondria
-therefore sensitive to oxidative damage
- however very flexible because of ankyrin and spectrin proteins attached to membrane

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6
Q

Other cells produced by haematopoiesis

A

Important to the immune response but not measured in a full blood count
Dendritic cells: professional antigen presenting cells found in tissues
Mast cells: produced in bone marrow but mature in tissues- very similar to basophils

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7
Q

Haematopoiesis

A

The process of blood cell production
Haematopoiesis starts 17 days after fertilisation and continues throughout life
Haematopoiesis is regulated by growth factors and cytokines
Haematopoietic tissues can respond rapidly to increase cell production (blood loss, infection) 1012 cells arise daily from bone marrow

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8
Q

Sites of haematopoiesis

A

Foetus: yolk sac moving to foetal liver
Infants: bone marrow virtually all bones
Adults- bone marrow, axial skeleton (red marrow)
Reduction in haematopoiesis with age

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9
Q

What is a stem cell

A

Can divide indefinitely so it can:
- replenish itself
- give rise to specialised, differentiated cells

Haematopoietic stem cells (HSC) are multipotent

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10
Q

Platelet production

A

Platelets arise from cytoplasm of megakaryocytes in bone marrow
2000-3000 platelets per megakaryocyte
Earliest progenitors look like myeloid blasts
The cells then enlarge due to nuclear divisions (endomitosis)
Regulated by thrombopoietin (TPO) = peptide- produced mainly by liver
TPO receptor (c-Mpl) on megakaryoblast, megakaryocyte and platelets

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11
Q

Leukaemia

A

Maturation arrest causes acute leukaemia
Block in haematopoiesis

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12
Q

Chronic myeloid leukaemia CML

A

No maturation arrest leads to over-production of mature cells
No negative feedback on haematopoiesis

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13
Q

Haematopoiesis- transcription factors

A

Proteins that control which genes are turned on or off by binding to DNA and promoting or blocking gene transcription

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14
Q

Increasing cell counts

A

Replacing cells in clinical use
-erythrocyte transfusion- lasts 1 month
-platelet transfusion- lasts few days
- Haematopoietic stem cells- stem cell transplants should last a life time

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15
Q

Growth factors in clinical use

A

Erythropoietin (recombinant)- subcut injections
Aim to improve anaemia so transfusions not needed
Mainly used for end stage renal disease (endogenous epo low as produced by fibroblasts in the kidney)
Can be used in:
- some cases of myelodysplasia (when endogenous epo not increased)
-pre-autologous blood donation
- Jehovah’s Witness (blood loss) recent case of helping patients undergoing cardiac transplant

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16
Q

Growth factors in clinical use

A

G-CSF (recombinant) subcut injections
Used for:
- prevention of infections in neutropenic patients, eg chemotherapy, congenital neutropenia
-to mobilise stem cells into peripheral blood for stem cell harvests for stem cell transplants

Thrombopoietin TPO receptor agonists:
- Romiplostim- subcutaneous injection (Amgen)
-Eltrombopag- oral- GlaxoSKB

Uses:
-idiopathic thrombocytopenia (autoimmune ITP)
-thrombocytopenia in: low risk myelodysplastic syndrome, post chemotherapy, aplastic anaemia (effects on stem cells not just megakaryocytes)

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17
Q

The full blood count

A

-Haemoglobin
Haematocrit/ packed cell volume
Red blood count
Mean cell volume (= PCV/RBC)
Mean corpuscular haemoglobin MCH (=Hb/RBC)
MCHC mean corpuscular haemoglobin concentration(=Hb/PCV)
: parameters that describe the size and haemoglobin content of RBCs
-reticulocyte count (red cell precursor)
- white blood count (and differential)
- platelet count

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18
Q

Polycythemia (too many)

A

Relative (dehydration or hypovolaemia)
Absolute:
-primary (polycythemia rubra Vera)
- secondary ( appropriate, inappropriate)

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19
Q

Anaemia (too few)

A

Many types
Classify by:
- MCV (mean corpuscular volume)
- cause- decreased production, increased loss

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20
Q

Blood groups

A

Antibodies against proteins (antigens) on the surface of red cells
ABO blood group is the most important but lots of others, everyone has antibodies to the ABO blood proteins that they dont have

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21
Q

White cell differential count

A

Granulocytes (polymorphonuclear cells):
- neutrophils
-eosinophils
-basophils

Mononuclear cells:
- lymphocytes
-monocytes (become macrophages)

Mast cells aren’t in the WCC- reside in tissues

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22
Q

Hierarchy of blood cells

A

Stem cell
Lymphoid lineage or myeloid lineage

Lymphoid-> T cell and B cell
Myeloid-> monocyte, neutrophil, erythrocyte, megakaryocyte

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23
Q

Neutrophils

A

Most frequent white cell in health, most of WCC
Too many:
- infection
-tissue infarction (death/necrosis)
-malignant i.e. chronic myeloid leukaemia
-physiological e.g. pregnancy

Too few:
- ethnic neutropenia
-congenital neutropenia
- reactive, especially viral
-bone marrow infiltration/ failure
-B12/ folate deficiency
- drugs

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24
Q

Lymphocytes

A

T cells, B cells, Natural killer cells
Too many:
- smoking
- splenectomy
- infection
-lymphoproliferative disorders

Too few:
- reactive
-drugs
- congential immunodeficiency
- HIV

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25
Q

Too many lymphocytes can be normal

A

REACTIVE:
- polyclonal i.e in response to multiple antigens and epitopes, this increase in numbers is appropriate to the threat, these extra cells die back to a baseline level through a process called apoptosis or programmed cell death

CLONAL:
- one precursor cell and its progeny
- linked to cancer

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26
Q

Platelets

A

Cytoplasmic blebs
Essential for clotting
Too many:
- reactive: infection, inflammation, infarction
-splenectomy
-iron deficiency
- bleeding
-myeloproliferative disorders eg essential thrombocythemia

Too few:
- immune thrombocytopenia purpura
- consumption
- splenomegaly
-alcohol
-liver disease
- bone marrow infiltration
-drugs
-genetic causes

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27
Q

Evaluating haematopoiesis- bone marrow

A

Aspirate/smear: the aspirate extracts semi-liquid bone marrow. This can be examined by light microscope, flow cytometry and chromosome analysis- quick

Biopsy: more painful, the trephine biopsy obtains a core of bone marrow good for looking at cellularity and marrow infiltration by histology and immunohistochemistry

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28
Q

Definition of anaemia

A

Reduction in haemoglobin (Hb)
the normal range of Hb is dependent on a number of factors:
- Gender- androgens can stimulate erythropoietin in men -Pregnancy- plasma volume
- extremes of age
-different labs/ Testing platforms
- altitude

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29
Q

Whats in the blood

A

Plasma: 55%, contains plasma proteins, electrolytes, hormones, nutrients, 91% of this layer is made up of water
Buffy coat: yellow or brown layer, contains platelets and white cells
Red layer: red blood cells

The buffy coat and red layer make up 45% of total volume

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30
Q

Red cells= erythrocytes

A

Biconcave structure
No nucleus
O2 and CO2 transport
120 day lifespan
Colour comes from an iron containing oxygen transport metalloprotein called haemoglobin in the cytoplasm

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31
Q

Erythropoiesis

A

Production of red blood cells
Pronormoblast is the precursor, then differentiates into normoblasts (erythroblasts), eventually into reticulocytes then red cells, decrease in size
Reticulocytes have extruded nucleus but still has RNA so can still make haemoglobin (not possible in erythrocyte)
During bleeding or haemolysis the bone marrow is stimulated to release red cells, often earlier progenitors released- reticulocytes in the blood-> indicates some red cells have been lost
Pronormoblasts and normoblasts have blue cytoplasm, salami appearance
No nucleus in reticulocytes and erythrocytes

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32
Q

Haemoglobin

A

Iron containing, oxygen transport protein
Hb made up of 4 polypeptide chains (tetramer)
1 heme molecule per chain
4 binding sites for O2
Hb chain variants:
- HbA, alpha2beta2, >95%
- HbA2, alpha2delta2, <3.5%
-HbF, alpha2gamma2, <1%
-HbS, alpha2Betas2, pathological >90% in sickle cell anaemia

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33
Q

Oxygen dissociation curve

A

Illustrates how RBCs carry and release oxygen, haemoglobin affinity for oxygen
-Left shit corresponds to higher affinity for O2: less able to release oxygen, pH high, temp low, low CO2, low 2,3DPG, foetal Hb
-Right shift corresponds to lower affinity for O2, more able to release oxygen, low pH, high temp, high CO2, high 2,3DPG, methaemoglobin, sickle Hb
A decrease in red cells results in permanent reduction in amount O2 that can reach tissues-> symptoms of anaemia

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34
Q

Symptoms of anaemia

A

Symptoms:
-Fatigue
-Breathlessness on exertion
-Palpitations
-Angina
Signs:
- pallor, skin can look green
-tachycardia
-bounding pulse
-flow murmur
-signs of heart failure
-Koilonychia- spooning of nails
- angular stomatitis- splitting and soreness at side of mouth
Clinical features depend on:
- Hb level
- Time taken to fall, can come on gradually and body compensates
-cause of anaemia
- other organ reserve e.g lungs, heart

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35
Q

Assessing pallor

A

Think about skin tone of patient
Best place to look is conjunctiva
If anaemic will be very pale not pink/red

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36
Q

Pathogenesis of anaemia

A
  1. Reduced production of red cells
  2. Increased destruction/loss/sequestration (splenomegaly, blood cells can be drawn into spleen)
  3. Poor functioning red cells
37
Q

Causes of anaemia 1

A

Reduced production:
Deficiencies in:
-Iron, dietary, malabsorptions, chronic blood loss
-B12 & folate, pernicious anaemia, alcohol/diet, increased cell turnover (cells use the body’s reserves of B12 and Folate)

Bone marrow pathology:
- aplastic anaemia- cells replaced by fat cells in bone marrow
- myelodysplasia- not developed properly
- myeloma - cancer

Displacement in bone marrow:
- leukaemia
-other cancers metastasising to bone
- myelofibrosis- fibrosis of bone marrow meaning haematopoiesis and erythropoiesis doesn’t occur properly

Chronic disease:
- renal failure
-myeloma
- chronic inflammatory conditions.

38
Q

Nutrients and anaemia

A

Iron: essential for haemoglobin production, absorbed in duodenum and proximal jejunum in ferrous Fe2+ state, stored as ferritin Fe3+ majority in bone marrow, liver and spleen

Folate and B12: folate is needed to turn uracil into thymidine, an essential building block of DNA- B12 is involved in this process , more than 95% of folate in the body is in the red blood cells, B12 is stored in liver, usually have around 4 months worth of folate and 3-5 years of B12 stored, producing excess red cells eg in haemolysis can result in folate deficiency

39
Q

GI causes of anaemia

A

Any inflammation or dysfunction of stomach, duodenum, liver, small or large bowel can cause malabsorption
Eg gastritis/ colitis
Pernicious anaemia/ Coeliac disease
Gastrectomy/colectomy

40
Q

Causes of anaemia 2

A

Loss of RBCs:
-haemolysis: immune or non immune
- splenomegaly
- bleeding

Poor function (mostly congenital also have haemolysis):
-RBC membrane defect- hereditary spherocytosis, hereditary elliptocytosis
-Haemoglobin defect (haemoglobinopathy)- sickle cell anaemia, thalassaemia
-RBC enzyme defect- G6PD deficiency, pyruvate kinase deficiency

41
Q

Hereditary spherocytosis

A

A defect in the red blood cell cytoskeleton
Causes RBC to contract to a sphere, no central pallor
- most surface tension efficient
- but least flexible configuration so gets damaged easily
Damaged cells get removed by macrophages in the spleen results in less RBCs causing anaemia
Autosomal dominant
Many different proteins: usually spectrin deficiency in red cell membrane, shorter RBC lifespan
Symptoms are exacerbated by inter current illness
Treatment: folic acid, splenectomy, rarely transfusion only if Hb very low

42
Q

Thalassaemia

A

Mostly autosomal recessive
Common in south Mediterranean, North Africa, Middle East and SE Asia
Defect in alpha or beta globin gene:
- results in abnormal form of Hb
- haemoglobinopathy
Severity depends on how many of the alpha or beta globin genes are missing
If only one gene missing= minor patient
Different Hb proteins can be identified by electrophoresis
1.5% pop are beta- thalassaemia carriers
Features of haemolysis:
- anaemia, dark urine, jaundice
- splenomegaly
Treatment varies form none to transfusion dependent

43
Q

Sickle cell anaemia

A

Autosomal recessive
Trait is asymptomatic
High prevalence west/North Africa
Defect of Hb beta globin gene, glutamic acid-> valine
Changes shape Hb
Obstructed capillaries -> painful crisis and end organ damage
Damaged and removed by spleen
Hyposplenism- small spleen, at risk infections
Treatment includes:
- exchange transfusion
-hydroxycarbamide- decreases WBC count and suppresses bone marrow production

44
Q

G6PD deficiency

A

X linked
Lack glucose-6-phosphate dehydrogenase
Important enzyme in the pentose phosphate shunt
Maintains reduced NADPH which is the RBCs only source of glutathione which mops up free radicals
Red cells unable to tolerate oxidative stress due to too many free radicals and haemolyse
- neonatal haemolytic anaemia
- Favism (fava beans)
- acute non spherocytic haemolytic anaemia
- drug induced haemolysis

45
Q

Investigating anaemia

A

Full history
Examination
Full blood count and film
Measure levels of ferritin, B12 and folate
Biochemistry: liver and kidney function - evidence of haemolysis increase in bilirubin
Haemolysis screen, e.g. cell turnover

46
Q

Using Hb and Mean cell volume MCV to diagnose anaemia

A

MCV gives mean red blood cell size
Low mcv: iron deficiency, thalassaemia, sickle cell disease
Normal mcv: chronic disease, acute blood loss, bone marrow failure
High MCV: B12 and folate deficiency, alcohol/drugs, haemolytic anaemia— reticulocytes are bigger

47
Q

Haemostasis

A

Mechanism that leads to the cessation of bleeding from a blood vessel

48
Q

Thrombosis

A

Local coagulation or clotting of the blood in a part of the circulatory system
Pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding
Can occur in the veins (venous thrombosis) and arteries (arterial thrombosis)
Venous thrombosis leads to congestion of affected part of body
Arterial thrombosis affects blood supply and leads to damage of the tissue supplied by the artery e.g MI or stroke
Emboli can be formed in either venous or arterial thrombosis and these travel through the circulation causing thromboembolism

49
Q

Venous and arterial system

A

Arterial system:
-high shear system
-platelets are critical
- an arterial thrombosis is therefore treated with anti-platelet drugs e.g. aspirin, clopidogrel, ticagrelor

Venous system:
- low shear system
-platelets play minimal role
- a venous thrombosis is treated using heparin, warfarin and novel oral anti-coagulants (NOACS)- eg rivaroxaban, apixaban

50
Q

Anticoagulants and antiplatelets

A

Medications that help prevent or reduce blood clots
Anticoagulants: slow down clotting process by interfering with proteins in the blood
Antiplatelets: prevent platelets from binding together to form a clot

51
Q

Primary and secondary haemostasis

A

Primary:
-formation of platelet aggregate within 5 minutes bleeding, seal area of damaged vessel wall

Secondary:
-formation of a stable fibrin clot occurs within 10 minutes bleeding

Both stages occur simultaneously

52
Q

Defects in primary haemostasis

A

Characterised by:
- purpura- skin haemorrhages- purple coloured spots
-petechiae
-easy bruising
-epistaxis - nosebleed
-gingival bleeding
-menorrhagia (heavy menstrual bleeding)
-gastrointestinal bleeding

Defect in patients in primary haemostasis results in excessive bleeding after trauma, surgical procedures, dental surgery

53
Q

Platelet vs coagulation disorder

A

Platelet disorder:
-Prototypic disorder: thrombocytopenia, platelet defect, VWD
-bleeding: intermediate
-petechiae: yes
- haemarthrosis (bleeding in joints): no
- haematomas: uncommon
-epistaxis: common
- menorrhagia: common

Coagulation disorder:
-prototypic disorder: haemophilia
-bleeding: delayed
-petechiae: no
-haemarthrosis: yes
-haematomas: common
-epistaxis: uncommon
-menorrhagia: uncommon

54
Q

Platelets

A

Small discs 1-3um
Anucleate
Lifespan- 10 days
Circulate as quiescent cells surveying the integrity of the vasculature
Dramatic change in morphology on activation (vessel wall damage)
Normal count: 150-400* 10^9/L
Platelet production controlled by the cytokine thrombopoietin TPO which is produced in the liver, TPO concentration is controlled by platelet binding, thereby self regulating platelet production

55
Q

Platelet production

A

Platelets come from megakaryocytes
Megakaryocytes have a polyploid nucleus which undergoes endomitosis
Megakaryocytes interact with sinusoidal endothelial cells in bone marrow and when they’re ready to release platelets, proplatelets extend into blood and platelets bud off into blood stream
Controlled by TPO, feedback system, self regulating platelet production

56
Q

Platelet structure

A

Contain many specialised organelles:
- alpha granules
-dense granules
- open canalicular system: allow platelets to spread
-microtubules: form round structure in cytoplasm to give platelets their round shape
-dense tubular system: where intracellular calcium is stored, the calcium is released into the cytoplasm when platelets are activated

57
Q

Platelets are powerful secretory cells

A

Dense granules:
-ADP and ATP: feedback molecules for platelet activation
-5-HT (serotonin)- this regulates vascular tone vasoconstriction
-polyphosphate: activates clotting system, - charged, electron dense

Alpha granules:
-fibrinogen and VWF: haemostasis
-PF4, SDF1alpha: chemokines
-TGFbeta: cytokines
-HGF, PDGF, VEGF: angiogenic
- thrombospondin: anti-angiogenic
- P-selectin, CD40L: membrane
-MMP-1, MMP-2 etc: metalloproteinases

When a platelet comes across vessel wall damage, degranulation occurs to restrict bleeding. When platelets are activated they undergo de novo synthesis of TxA2 (powerful platelet agonist that stimulate platelets)

58
Q

Vascular endothelium

A

Has classical monolayer cobblestone morphology
It produces:
-regulators of clotting e.g. NO and prostacyclin
-CD39 which mops of ADP and ATP
-molecules that inhibit clotting eg thrombomodulin, TFPI, heparin, plasmin
-they produce molecules that activate clotting eg tissue factor and VW factor
When they become activated they express adhesion molecules meaning leukocytes and platelets can interact with vessel wall

59
Q

Platelets haemostasis the Normal process

A

Vascular endothelium lines blood vessels
Produces substances that keep platelets quiescent
Platelets because of their small disc shape get marginated towards the vessel wall this means they’re constantly communicating with endothelium
- injury to blood vessel exposes subendothelial collagen
-VWF will bind to exposed collagen
-VWF provides a bridge to which platelets can bind to vessel wall
-this results in activation of platelets
-they degranulate and begin forming platelet aggregates which seal the area of the vessel wall damage to limit bleeding
- the platelet plug then forms within minutes,
-platelets provide surface for which thrombin is generated. From thrombin, fibrin is formed which allows for stabilisation of the platelet plug

60
Q

VWF

A

Von Willebrand factor
-polymer synthesised and secreted by endothelium and megakaryocytes
-a carrier of factor VIII
-acts to anchor platelets to sub endothelium
-it also forms bridge between platelets
- regulated by an enzyme (VWF protease) which cleaves the molecule and breaks it down into classic multimer forms
-its the biggest forms of VWF that are most effective in promoting platelet adhesion
-some patients have a defect in protease TTP defect
- if enzyme is absent then we get no cleavage of VWF so we just get big forms
-this spontaneously causes platelet aggregation and spontaneous aggregates in organs and skin

61
Q

VWF mechanism

A

In a damaged blood vessel wall, VWF (circulates in blood) binds to the exposed collagen
VWF undergoes a conformation change (under shear conditions) to become a filament shape and by doing so, exposes binding sites for the receptor GP1b found on platelets
When platelets bind to the binding sites of VWF they slow down and roll across area of damage, This then promotes aggregation

62
Q

Direct platelet adhesion

A

Once the platelets start rolling, slowing down and interacting with VWF other receptors come into play
GP6 and alpha2beta1 (integrin) receptor on platelets allow the platelets to directly bind to the collagen
Mechanism:
-the binding of the platelet GP6 receptor to the collagen causes platelet activation to occur
-this activation allows the alpha2beta1 molecule to open its binding site for collagen and allow for firm adhesion

63
Q

Amplification mechanism

A

-signal transduction, occurring through membrane receptors on platelets, allows for the liberation of calcium from dense tubular system
-this promotes platelet activation, secretion and changes in cytoskeleton of platelets allowing them to change shape
- secretion involves the secretion of: dense granules which release ADP, ATP, 5-HT. alpha granules which release many proteins including VWF.
-platelets also make de nova TxA2 via a chemical pathway and release this as well
-ADP, ATP, 5-HT and TxA2 have their own GPCR on platelet surface
-these act in a positive feedback loop to the original and other platelets
-this allows for amplification which attracts other platelets to the vicinity and allows for the formation of a platelet plug
-thrombin is also produced and feedbacks the same way

64
Q

Thromboxane formation

A

When platelets are activated you get release of intracellular calcium from dense tubular system activates PLA2 enzyme
This enzyme liberates arachidonic acid from membrane bound phospholipids
COX1 converts the arachidonic acid to cyclic endoperoxidases and then TX-synthases converts them into TxA2
TxA2 is released and binds to its own receptor on the platelet TxA2 receptor
Defect in any enzymes above will result in mild bleeding disorders
COX1 is the target of aspirin and other NSAIDS it binds to COX1 and irreversibly inhibits it. So taking low dose aspirin every day can prevent all platelets in system from producing TxA2 (important anti-thrombotic)

65
Q

ADP signalling

A

ATP receptors are called P2X receptors
ADP receptors are called P2Y receptors
- there are P2Y receptors—> P2Y12 and P2Y1
These are GPCRs
Binding of ADP to P2Y1 receptor allows for activation PLC enzyme
Binding ADP to P2Y12 allows for inhibition of cAMP production
As as result we are promoting platelet aggregation and shape change simultaneously
ATP promotes liberation of intracellular calcium which is important for downstream biochemical processes
Drugs such as clopidogrel, prasugrel, ticagrelor, cangrelor target P2Y12 and then inhibit platelets in patients in high risk of thrombosis. These stop ADP interacting with P2Y12

66
Q

Alpha2Beta3 receptor

A

It’s an integrin
Integrins in their resting conformation cannot bind to their ligand
The two molecules GP3a and GP2b that make up the integrin have binding site for ligands. They have RGDs binding site (GP3a) and dodecapeptide binding site (GP2b)
They’re initially buried so molecule has to open up via inside out signalling when platelet are activated to allow for binding of the ligand
The ligand in question in fibrinogen
Fibrinogen forms bridges between adjacent activated platelets via alpha2beta3 receptor
So we start to get aggregation occurring to form thrombus
Alpha2beta3 can also bind to proteins eg VWF

67
Q

Platelet shape change

A

Exposure of collagen causes the platelet to start rolling
The platelets then spreads and undergo firm adhesion (shape of Mexican hat)

68
Q

Platelet activation: procoagulant surface

A

When platelets are fully activated we get the exposure of procoagulant surface of platelets
Resting platelets dont have this as the negative charged phospholipid are mainly found on the inner leaflet of the cell membrane
Therefore you cannot activate the clotting system of resting platelet
However when we get full platelet activation you get liberation of high level of intracellular calcium and this activates scramblase enzyme which results in exposure of negatively charged lipids on platelet surface
This means through calcium the vitamin K clotting factors (factors 2,7,9,10) will bind through their carboxyl group through calcium bridge onto surface of platelets
This results in generation of lots of thrombin and fibrin formation as end result of clotting
Thrombin will also feedback and activate platelets via par receptors

69
Q

Secondary haemostasis: clotting cascade

A

The clotting cascade is a very controlled amplification system
Small amounts of certain molecules allow for the generation of large amounts of thrombin: concentration of molecules as you go down cascade increase
- thrombin (serine proteases) converts soluble fibrinogen to insoluble fibrin. It also activates factor 13 to factor 13a which cross links fibrin polymers being formed
-fibrin will cross link and form polymers. Factor 13 mediates the cross linking creating a stable fibrin clot
We have a surface contact (intrinsic in blood) pathway and extrinsic (tissue damage out blood) pathway both these pathways converge on factor 10 to converting it to factor 10a
- extrinsic pathway is activated via release of tissue factor this activates factor 7 which becomes part of the complex to activate factor 10a
-intrinsic pathway: factor 12-12a. 12a converts 11 to 11a. 11a converts 9 to 9a factor 9a, 8 and PL and Ca2+ form the 10a complex on the platelet surface and this produces 10a
Factor 10a converts prothrombin to thrombin . In order to achieve this factor 10a needs calcium, phospholipids and cofactor V to drive it. This is called a prothrombinase complex

70
Q

Mechanisms which prevent intravascular clot formation

A

Unobstructed, non-turbulent blood flow
Intact vascular endothelium
Circulating anticoagulant proteins:
- antithrombin, protein C/S

71
Q

Protein C activation

A

Thrombin interacts with vessel wall via thrombomodulin receptor
This activates protein c to form activated protein C
Protein C works with its cofactor- protein S
These form a complex which is really important in regulating clotting
Activated protein C will bind to factor 5a and 8a and break them down
These are cofactors in the prothrombinase and 10ase complex so these complexes no longer form
If you deactivate these clotting molecules then you stop clotting via stopping generation of fibrin

72
Q

Coagulation cascade

A

Tissue factor can be expressed on circulating monocytes and endothelial cells when they are activated
TF pathway inhibitor TFPI stops factor 7a from activating factor 10 and thrombin generation
Antithrombin (in presence of heparins) inhibits thrombin
It also inhibits factor 10a, 9a, 7a, 12a, 2a
Protein c and s attack cofactors 5 and 8 in prothrombinase and 10ase complex
Finally when fibrin is formed it is insoluble but can be broken down via fibrinolysis and this releases fibrin degradation product

73
Q

Fibrinolysis

A

The enzymatic breakdown of the fibrin in blood clots
If there’s a lot of thrombin around it will activate the vessel wall and release TPA (tissue type plasminogen activator) which binds to fibrin and helps in the conversion of plasminogen to plasmin
Plasmin breaks down the fibrin which breaks down the clot and you get release of FDPs

74
Q

Disorders predisposing to venous thrombosis

A

Hereditary:
- factor v Leiden mutation- stops ability of activated protein c to breakdown factor 5
-prothrombin gene mutation
-antithrombin deficiency
-protein C deficiency
-protein S deficiency

Acquired:
-the lupus anticoagulant

75
Q

Targets for anticoagulant drugs

A

Heparins and LMWH: target thrombin and 10a
Vitamin K antagonists (warfarin): target vitamin k clotting factors 2,7,9,10
Direct thrombin inhibitors
Direct factor 10a inhibitors

76
Q

Laboratory tests used to investigate the haemostatic system

A

Platelet count
Prothrombin time
Activated partial thromboplastin time
Fibrinogen level
Coagulation factor assays
Platelet aggregation studies
Molecular biology

77
Q

Platelet count

A

Normal platelet count- 150-400 10^9/L
Above 40: spontaneous bleeding uncommon, bleeding only occurs after trauma/lesion, if spontaneous bleeding occurs then there may be an associated platelet function coagulation defect
Below 40: bleeding is common not always present
Below 10: sever bleeding
Platelet transfusion threshold is now set at 1010^9/L

78
Q

Thrombocytopenia

A

Inherited
Drug induced
Bone marrow failure
Hypersplenism
Other causes
Lymphoma
HIV virus
Idiopathic thrombocytopenia purpura ITP

79
Q

Congenital platelet disorders

A

Disorders of adhesion: Bernard-Soulier syndrome (defect in GP1B- molecule that binds platelets to VWF)
Disorders of Aggregation: Glanzmann thrombosthenia: defect in GP2B3A
Disorders of granules:
-grey platelet syndrome: defect in alpha granules
-storage pool deficiency: defect in ability to store molecules in descending granules
-Hermansky-Pudlak syndrome: defect in dense bodies
-Chediak-higashi syndrome

80
Q

Tests of clotting pathway

A

Use prothrombin time PT as a measure of extrinsic pathway, PT used to evaluate clotting factors 7,10,5,2,1
We use aPTT (activated partial thromboplastin time) as a measure of intrinsic pathway aPTT evaluates clotting factors 7,9,11,8,10,5,2
What is their use:
Finding a fault in the system, monitoring response to replacement of clotting factors eg after FFP, monitoring effect of anticoagulants

81
Q

Finding the fault

A

If aPTT is prolonged then clotting factor 8,9,11,12 may be reduced
If PT is prolonged then factor 7 reduced
If both are prolonged then factor 2,5,10 and fibrinogen are reduced

82
Q

Defects of the haemostatic system causing a bleeding tendency

A

Hereditary:
-clotting factor deficiencies: factor 8- haemophilia A. Factor 9-haemophilia B. Fibrinogen, prothrombin, FV, FVII, FX, FXI (FXII), FXIII
-Von Willebrand disease
-platelet disorders: Glanzmann thrombasthenia, Bernard-Soulier syndrome

83
Q

Coagulation factor deficiencies

A

Sex linked recessive:
- factors VIII (haemophilia A) and IX (haemophilia B) deficiencies cause bleeding
-prolonged aPTT, PT normal
-usually occurs in boys and women are carriers
Autosomal recessive (rare):
-factors II,V,VII,X,XI, fibrinogen deficiencies cause bleeding and prolonged PT and/or aPTT
-factor XIII deficiency is associated with bleeding and impaired wound healing, PT/aPTT normal; clot solubility abnormal
-factor XII, prekallikrein, HMWK deficiencies do not cause bleeding

84
Q

Von Willebrand disease: clinical features

A

Von Willebrand factor VWF
Synthesised in endothelium and megakaryocytes
Forms larger multimers> 20 million daltons
It’s a carrier of factor VIII
Anchors platelets to subendothelium
Also forms bridge between platelets
Disease:
-inheritance is autosomal dominant (mostly types 3 is recessive) so affects males and females
-incidence ~1% most common bleeding disorder
-mucocutaneous bleeding pattern

85
Q

Laboratory evaluation of Von Willebrand disease

A

Classification:
-type 1: partial quantitative deficiency
-type 2: qualitative deficiency- loss of high molecular weight multimer so molecule becomes less efficient at mediating haemostasis
-type 3: total quantitative deficiency
Diagnostic tests:
VWF antigen, VWF activity , multimer analysis
Type 3; everything is missing
Type 2: antigen is normal but activity low because largest multimer missing
Type 1: things are low but not absent

86
Q

Antiplatelet therapy

A

Effective in preventing thrombotic complications
Families of drugs with proven clinical efficacy
-COX1 inhibitors eg aspirin
-ADP receptor antagonists eg clopidogrel, prasugrel, ticagrelor
-GpIIb/IIIa antagonists eg abciximab, eptifibatide, tirofiban
PAR-1 antagonists eg vorapaxar, atopaxar

Monotherapy: secondary prevention of MI/stroke
Combination therapy: ticagrelor/aspirin- acute coronary syndrome patients undergoing percutaneous coronary intervention PCI and atrial fibrillation AF

87
Q

Leukaemias

A

Are cancers of haematopoeitic cells which arise in the marrow and spread to involved blood and lymph nodes/spleen

88
Q

Lymphomas

A

Cancers of cells in lymph nodes/spleen which spreads to involve bone marrow and blood

IIH (10 decks)

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