Week 1 Flashcards

Question

Too many lymphocytes can be normal

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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.

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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)

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

-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

Answer 40

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)

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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 10*10^9/L

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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

Answer 58

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

Answer 59

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

Answer 60

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

Answer 61

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

Answer 62

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

Answer 63

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

Answer 64

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

Week 1 Flashcards

(88 cards)