Haem

Question 1

Formation of unstable platelet plug

Answer 1

When endothelium is disrupted, collagen in the basement membrane is exposed
Von Willebrand factors bind to this
Glycoprotein 1-b receptors on platelets bind to VWF
Glycoprotein 1-a receptors bind directly to collagen
When platelets bind they’re activated, and they release ADP and thromboxane
This further activates the platelets and activates Glycoprotein IIb/IIIa, allowing fibrinogen to bind

Question 2

Normal platelet count range

Answer 2

150-400x 10^9/L

Question 3

Where coagulation proteins are made

Answer 3

Mostly liver
Some- VWF are made in endothelial cells
Some- Factor 5 and VWF megakaryocytes

Question 4

Extrinsic Pathway

Answer 4

Smooth muscle contains tissue factors- which contacts blood when there’s damage
TF initiates the clotting cascade- binds to factor 7 converting to 7a
This then converts 10 to 10a
10a then converts prothrombin to thrombin- which then further activates platelets

5a helps 10a convert prothrombin to thrombin faster
8a accelerates conversion of 10 to 10a

Thrombin converts fibrinogen(soluble) to fibrin(2 cleavages) forming a fibrin clot
Thrombin also activates 13 to 13a- which can crosslink the clot

Question 5

Action of warfarin

Answer 5

Glutamic acid residues in the clotting factors are converted into y-carboxyglutamic acid via vitamin k
Warfarin antagonises the action of vitamin k through inhibiting vitamin-K epoxide reductase

Question 6

Action of Heparin

Answer 6

Accelerates natural plasma inhibitor- antithrombin

Antithrombin inhibits the coagulation proteases: thrombin, 10a, 9a and 11a

Question 7

Lab tests for blood coagulation

Answer 7

Activated partial thromboplastin time- screening for causes of bleeding disorders
Prothrombin time- monitor heparin therapy in thrombosis
Thrombin time- monitor warfarin

Question 8

Fibrinolysis

Answer 8

involves activation of plasminogen by tissue plasminogen activator(tPA)
These are plasma proteins- plasminogen is a zymogen and tPA is a proteinase
tPA turns plasminogen into plasmin

Question 9

Protein C and S

Answer 9

Thrombin-TM complex on EC activates protein C
Protein C inhibits thrombin generation by inactivating cofactors Va and VIIIa

Thrombin binds and activates protein C, cleavage it and producing APC (serine protease)
Protein S is a cofactor for protein C

Question 10

Epistaxis

Answer 10

Nosebleed

Question 11

Significant elements of bleeding history

Answer 11

Epistaxis >10mins
Cutaneous haemorrhage or bruising without apparent trauma
Prolonged bleeding from wounds, spontaneously in 7 days after made
Spontaneous GI bleeding causing anaemia
Menorrhagia- heavy menstruation

Question 12

Primary haemostats

Answer 12

Formation of unstable platelet plug

Question 13

Secondary haemostasis

Answer 13

Stabilisation of plug with fibrin

Question 14

Problem with platelets

Answer 14

Low or impaired platelet function

Low- bone marrow failure accelerated clearance, pooling and destruction in enlarged spleen

Impaired- hereditary absence of glycoproteins, acquired due to drugs

Question 15

Auto-Immune Thrombocytopenia Purpura (auto-ITP)

Answer 15

Antibodies against platelets

Question 16

Causes of thrombocytopenia

Answer 16

Failure of production by megakaryocytes
Shortened half life
Increased pooling in enlarged spleen

Question 17

Types of platelet impairment

Answer 17

Glanzmann’s thrombasthenia: rare, autosomal recessive disorder, in which GpIIb/IIIa is lacking.
Bernard Soulier syndrome: autosomal recessive, lack of Gp1b.
Storage Pool Disease: broad term, referring to issues with granular storage and release.

Question 18

Von Willebrand Disease

Answer 18

Hereditary
Type 1- deficiency
Type 2- abnormal function

Question 19

Usual symptom in thrombocytopenia

Answer 19

Petechiae

Question 20

Test for disorders of primary haemostasis

Answer 20

Platelet count or morphology

Assay of VWF

Question 21

Haemophilia

Answer 21

Genetic-A/B- Factor 8 or 9 deficiency
Acquired- Liver disease, drugs, dilution, consumption

Delayed bleeding since primary plug is formed

Question 22

Disseminated intravascular coagulation

Answer 22

Small clots develop in the blood- blocking small vessels
Generalised activation of coagulation
Depletes coagulation factors and platelets
Activation of fibrinolysis depletes fibrinogen- causes deposits which causes organ failure

Question 23

Hallmark of haemophillia

Answer 23

Haemarthrosis

Bleeding in the joints

Question 24

Tests for disorders of secondary haemostasis and results

Answer 24

Screening- Prothrombin Time, Activated Partial Thromboplastin (aids conversion of prothrombin) Time and full blood count
Factor assays

APTT is prolonged in haemophilia since not making factor 8 or 9
PT will be normal

Question 25

Causes of disorders of fibrinolysis

Answer 25

Hereditary- antiplasmin deficiency | Acquired- drugs such as tPA, Disseminated intravascular coagulation

Question 26

Genetics in Bleeding disorders

Answer 26

Haemophilia- sex linked- A and B both sex linked VW Disease- autosomal- type 1 autosomal dominant, 2 recessive Others- autosomal recessive, less common

Question 27

General Treatment of abnormal haemostasis

Answer 27

Failure of abnormal production- Replace missing factors/platelets Stop drugs causing problems Immune- Immunosuppression Splenectomy for ITP Increased consumption- Treat the cause of DIC Replace

Question 28

Factor replacement therapy for bleeding disorders

Answer 28

Plasma- contains all coagulation factors Cryoprecipitate- rich in fibrinogen and FVIII, VWF, FXIII Factor concentrates- all available apart from 5

Question 29

Drugs for haemostatic treatment

Answer 29

DDAVP- vasopressin derivative Causes 2-5 times increase in VWF and VIII Given intranasally or intravenously Tranexamic acid- inhibits fibrinolysis- competitively inhibits binding of tPA to fibrin

Question 30

Iron homeostasis

Answer 30

Need 20mg of iron a day, but it is badly absorbed as can only be absorbed in Fe3+ state Iron is recycled when RBC break down though

Question 31

Absorption of iron

Answer 31

Absorbed from gut lumen into cells Ferroportin- iron transporter protein allowing entry to blood Once in blood binds to transferrin As pH drops iron is released and transferrin receptors are recycled

Question 32

Hepcidin

Answer 32

Hormone that controls iron homeostasis Binds to enterocytes and induces depredation of ferroportin Iron stuck in cell and when cell is shed it's effectively lost

Question 33

Anamia of chronic disease and causes

Answer 33

``` Aneamia in patients who are unwell Cytokine release due to being unwell Cytokines prevent usual flow form duodenum to RBC Block erythropoietin increasing Stop iron flowing out cells Increase production of ferritin Increase death of RBC ```

Question 34

Causes of iron deficiency

Answer 34

Bleeding Increased use- rapid growth/pregnancy Dietary deficiency Malabsorption of iron- coeliac

Question 35

Investigating iron deficiency anaemia

Answer 35

Mean cell volume Serum Iron- low, but it is low also in ACD. Hb electrophoresis confirms thalassaemia trait Ferretin- low in iron deficiency and high in chronic disease Transferrin-high, normal in ACD Transferrin saturation-low

Question 36

Necessity of folate and B12

Answer 36

Both required for DNA synthesis and integrity of nervous system Both needed for production of deoxythymidine, which is crucial in DNA synthesis

Question 37

Clinical features of Vitamin B12 and foot deficiency

Answer 37

Rapidly dividing cells effected Effect worse in bone marrow, epithelial surfaces of mouth/gut Causes anaemia- causing tiredness and shortness of breath Causes Jaundice Can cause GI problems, resulting in glossitis and angular cheilosis (inflamed mouth corners)

Question 38

Type of anaemia B12 or folate deficiency causes

Answer 38

Macrocytic- high MCV Megaloblastomic-morphoogical change due to DNA not being produced normally, so may see blue cytoplasm with no nucleus or pink with This also causes hypersegmented neutrophils

Question 39

Homocysteine problems with B12 deficiency

Answer 39

B12 converts homocysteine to methionine But when deficient- high homocysteine which is toxic- and at high levels is associated with atherosclerosis and premature vascular disease Middle elevated levels are associated with CV disease and thrombosis

Question 40

Nuero problems associated with B12 deficiency

Answer 40

Bilateral peripheral neuropathy Subacuate combined degeneration of the cord (posterior and pyramidal tracts of the spinal cord) Optic atrophy Dementia

Question 41

Causes of B12 deficiency

Answer 41

Poor absorption- (post gastrectomy, gastric `trophy, AB to IF, diseases of small bowel) Reduced dietary intake- stores last 3-4 yrs Infections/infestations

Question 42

B12 absorption

Answer 42

2 methods 1: Slow and inefficient (1%) Direct across intestinal wall 2: Combines with intrinsic factors and is absorbed

Question 43

Pernicious Anaemia

Answer 43

Autoimmune condition Severe lack of intrinsic factors B12 deficient

Question 44

Drugs causing B12 deficiency

Answer 44

Metformin- used in diabetics and PCOS Proton pump inhibitors Oral contraceptive pill

Question 45

Testing for B12 deficiency

Answer 45

Measure methylmalonyl acid Measure homocysteine Look for anti IF AB Used to do Shilling test Replenishes stores of B12 Drink radioactive B12, if abnormal not in urine since cannot absorb

Question 46

Treatment of B12

Answer 46

Injections of B12 3 times a week for 2 weeks After injections every 3 months

Question 47

When to use blood

Answer 47

May when someone suffers a massive bleed | Anaemic patients if B12/iron/folate not appropriate

Question 48

ABO Blood groups

Answer 48

Always a H stem attached to the membrane Either A or B stems- O is neither only H These antigens are formed by adding sugar residue to common glycoprotein and fructose stem

Question 49

Genes for ABO

Answer 49

A GENE: codes for N-acetyl galactosamine transferase (adds N-acetyl galactosamine to stem) B GENE: codes for galactose transferase (adds galactose to common glycoprotein and fucose stem) A and B genes are co-dominant – if you have both genes you will code both chains The O group is recessive – some people carry O and A/B

Question 50

ABO Antibodies

Answer 50

Produce antibodies against any antigens not present on our own RBC Naturally occurring IgM So if patient receives incorrect ABO transfusion, often fatal since IgM go through complement cascade- haemolysis

Question 51

Testing for blood types

Answer 51

Use IgM antibodies | If there is agglutination it is incompatible

Question 52

RH blood groups

Answer 52

RhD- most important RhD positive if have D antigen, negative if not D- dominant- codes for D antigen

Question 53

RhD antibody

Answer 53

IgG Response on second exposure Doesn't cause death since IgG doesn't go through complement cascade- slower haemolysis

Question 54

Haemolytic disease of the new born

Answer 54

If RhD- mother has anti-D transfusion, and in the next pregnancy the foetus is RhD+, the mother's IgG AB cross the placenta- causing haemolysis which can cause hydros fetails and death

Question 55

Impotance of O-

Answer 55

Anyone can be transferred this blood, so can be used in emergencies when blood group isn't known

Question 56

Other RBC antigens and their clinical importance

Answer 56

There are other antigens present- but these aren't routinely matched However 8% of patients will form AB against some of these antigens So therefore have to test blood for RBC AB and give them antigen negative if have responded

Question 57

Why split blood into components

Answer 57

More efficient since patients don't need all components Some components degenerate quickly if stored as whole blood Removing plasma allows less fluid overloading in patients Red cells, plasma and buffy coat(WNC, platelets)

Question 58

Fresh frozen plasma(FFP) | And when to give it

Answer 58

``` Freeze to preserve coagulation factors Stored at -30 for 2 years Thaw out 20-30 mins before use Give 12-15ml/Kg May contain AB, won't kill but can cause some haemolysis ``` Give to those who have abnormal coagulation factors- may be bleeding or abnormal coagulation tests Can use to reverse warfarin

Question 59

Cryoprecipitate | And when it is used

Answer 59

Precipitate left in FFP after thaws Contains fibrinogen and FVIII Used in massive bleeds- when fibrinogen is low Can be used in people who have low fibrinogen frothier reasons and in rare conditions such as hypofibrinogen

Question 60

Platelets in transfusions | And when are they used

Answer 60

1 pool from 4 donors Shelf life 5 days Given to same ABO group since platelets have low level ABO antigens and can cause RhD sensitisation Given in haematology patients with bone marrow failure Massive bleeding or acute DIC Given for cardiac bypass surgery and the patient is on anti-platelet drugs

Question 61

Fractionated products

Answer 61

Factor VIII and IX- for haemophilia A and B respectively VIII for VWD Immunoglobulins- IM soecufuc tetanus, anti D, rabies IV Ig- broad mix of antibodies, pre-operative in patient with ITP or AIHA Albumin- useful in burns For certain liver and kidney conditions If kidney tubes become porous, proteins excreted

Question 62

Donors- what they are tested for

Answer 62

``` Must test for infections Hep B Hep C HIV HTLX Syphillis Hep E ``` Tests are not 100%, therefore exclude high risk donors