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PHYSIOLOGY PRIMARY > Haematology > Flashcards

Haematology Flashcards

1
Q

What are the constituents of blood?

A

plasma = 55% - water, electrolytes, plasma proteins, clotting factors

RBC = 45%

platelets 0.5% - travel near edges

white cells

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2
Q

Describe the structure of a platelet…

A

spindle shaped
2-4um
no nucleus
extensive cytoplasm

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3
Q

Describe the production of platelets. what is life expectancy and how are they removed?

A

Thrombopoietin from liver/kidney during inflammatory states

causes megakaryocytes in bone marrow to differentiate into platelets

life expectancy = 7-10days
removed by macrophages in spleen

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4
Q

What is Von willebrand factor

A

strand like protein
when inactive remains curled up
when exposed to turbulent flow/sheer stress unwinds by mechanical force

can bind collagen and platelets to help platelet adhering to area of vessel wall injury.

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5
Q

normal values for WBC, Hb, Platelets , haematocrit , MCV

A

Hb 130-170 men, 115-150 women (g/L)
platelet 150-400 x 10^9 per L
MCV 80-100
haemocrit 0.4 to 0.5
WCC 4-10 x 10^9 /L

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6
Q

what is haemostasis?

A

the physiological process of stopping bleeding and first stage of vessel repair.
consists of 3 major steps
- vasoconstriction,
- platelet plug formation
- formation of fibrin clot (via coagulation cascade)

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7
Q

Give an overview of the process of haemostasis

A
  1. vessel injury and bleeding
  2. vasospasm - mediated by endothelin - reduces blood loss and blood flow
  3. collagen from vessel wall (subendothelial) exposed
  4. PLATELET ADHESION: vWF is circulating in blood curled up (also present in endothelium) sheer stress of wall injury (turbulent flow) causes it to unwind exposing binding site for platelets GP1b receptor and collagen. hence vWF bridges collagen and platelets allowing platelets to aggregate at site of injury
  5. PLATELET ACTIVATION: the binding of GP1b to vWF activates platelets. also other factors activate platelet. (thromboxane, ADP, Thrombin, GPIIa/IIIb - positive feedback mechanism).
  6. Activation results in release of dense bodies (ADP , Ca) and alpha granules (vWF, fibrinogen) and other mediators (thromboxane, 5HT3). Positive feedback mechanism to activate more platelets and more adhesion/ aggregation.
  7. PLATELET AGGREGATION - activation results in fibrinogen release and GPIIb/IIIa activation. now vWF and fibrinogen can bind this receptor and cause aggregation of platelets through bridging.
  8. FIBRIN FORMATION - mean while clotting cascade has activated and produces factor IIa. This converts fibrinogen to fibrin to stabilise the clot!
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8
Q

What can activate platelets and what does this result in?

A

Activation of platelets
- GP1b and vWF binding
- GPIIb/IIIa binding fibrinogen/vWF
- thromboxane A2 receptor - thromboxane is released as part of inflammation from arachidonic acid pathway & released by platelets.
- ADP - released by platelets binds P2Y12 (GPCR) - results in platelet activation.
- Thrombin via PAR receptor

activation results in release of ..
- alpha granules - fibrinogen and vWF - strengthen clot
- dense bodies - ADP, Ca
- other mediators

outcome…
a lot of the mediators result in positive feedback for more platelet activation

fibrinogen/vWF - aggregation and strengthening of platelet plug

Ca - bridges between negative clotting factors and negative charges on platelet membrane to bring 2 pathways in physical contact

thromboxane, 5HT3 cause vasoconstriction

ADP binding P2Y causes cytoskeletal changes

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9
Q

what is the coagulation cascade

A

Divided into intrinsic and extrinsic pathway

consists of a cascade of proteolytic enzymatic reactions which results in amplification at each stage such that high quantities of thrombin are made

the main goal is to produce factor IIa (Thrombin) which catalyses fibrinogen to fibrin to stabilise the platelet plug and create a clot (soluble fibrinogen to insoluble fibrin)

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10
Q

Describe steps of coagulation cacade

A

Extrinsic pathway
- Tissue damage causes activation of factor III (tissue factor) to IIIa
- IIIa –> VIIa

Intrinsic pathway (triggered by mediators in blood e.g. Ca)
- F12 –> F11 –> F9 –> F8

  • 3a, 7a (extrinsic) form complex which can catalyse X to Xa
  • F8a is a cofactor for F9a (intrinsic) which also catalyses X to Xa

Xa –> 2a

2a –> fibrinogen to fibrin

fibrin polymerises - insoluble - strong clot

factor 13 forms cross bridges within fibrin to stabilise further

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11
Q

what are the fibrin , thrombin, TF , Ca known as in terms of the clotting factors..

A

Fibrinogen - factor 1 (fibrin 1a)
Thrombin = 2/2a
TF = 3/3a
Ca = factor 4

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12
Q

what is meant by secondary homeostasis ?

A

this describes the second part of haemostasis whereby platelet plug is matured by cleaving fibrinogen to fibrin tpo form a clot.

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13
Q

where is tissue factor found?

A

extracellular matrix of smooth muscle within vessel wall so exposed when vessel is damaged

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14
Q

what are the roles of thrombin?

A

cleaves fibrinogen to fibrin - stabilises clot

activates factor 13 which forms cross bridges to further stabilise the clot

can also activate more of the previous factors - positive feedback

bind PAR receptor on platelets to activate platelets

activates protein C - controls the amount of clotting by inhibiting clotting factors 5 and 8

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15
Q

what can inhibit platelet aggregation/activation?

A

NO
prostacyclin

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16
Q

what is the difference between PT and APTT?

A

PT = prothrombin time = test of extrinsic pathway (add tissue factor to sample and time how long for clot to form)

APTT = activated partial thromboplastin time = test of intrinsic pathway (add phospholipids and an activator to see how long it takes clot to form)

both also test common pathway

one T = the other T is an ex so its on its own.

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17
Q

what is the role of vitamin K

A

responsible for activation of clotting factors - gives them a negative charge such that Calcium can bridge them to platelets

gamma-glutamyl carboxylase - adds carboxyl group to create this negative charge

vitamin K is oxidised in this reaction and needs to be recycled via vit K epoxide reductase

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18
Q

normal value for PT and APTT

A

PT = 12-13 sec
APTT = 30-50 sec

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19
Q

what is the thrombin time?

A

thrombin added to sample and time how long the common pathway takes

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20
Q

why may factor Xa assays be measured?

A

see effectiveness of LMWH
particularly useful for those in extremes of weights were may not be getting the full benefit.

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21
Q

what is an INR?

A

international normalised ratio

ratio of PT compared to average PT of a control sample

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22
Q

what increases PT?

A

anything affecting common pathway
- Xa inhibitors- factor x
- LMWH - factor X and II
- Warfarin / liver disease / vit K deficiency - factor 10, 2

anything affecting extrinsic
- warfarin - factor 7

DIC - consumption of clotting factors

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23
Q

what increases APTT?

A

Anything affecting common pathway
- Xa inhibitors- factor x
- LMWH - factor X and II
- Warfarin / liver disease / vit K deficiency - factor 10, 2

intrinsic pathway -
haemophilia - 8 or 9

DIC

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24
Q

what might delay thrombin time?

A

thrombin time is just measuring common pathway - adds in thrombin and measures how long. so anything below this that is abnormal can cause issues.
e.g. fibrinogen deficiency

heparin and dabigatrin as these block thrombin (IIa)

25
Q

What is fibrinolysis?

A

the breakdown of a clot whereby fibrin is degraded by plasmin

plasminogen –> plasmin (protease)

much slower than coagulation/ clot formation and hence allows vessel to heal.

activated by tissue plasminogen activator (tPA) which is slowly released from damaged tissue which converts plasminogen to plasmin

26
Q

what is d dimer?

A

by product of breakdown of fibrin clot

27
Q

what is thrombolysis?

A

This is a medical management whereby the fibrinolysis pathway is utilised to breakdown a life threatening clot. (P.E, MI, limb ischaemia, stroke)

e.g. thrombolytic drugs include alteplase, streptokinase

28
Q

what is ROTEM?

A

Diagnostic test to evaluate the haemostatic process in whole blood to aid transfusion therapies
provides a evaluation of clot formation, stabilisation and dissolution

a sample of blood is rotated and causes blood to clot which changes the viscoelastic properties of the sample which can be measured by resistance to rotation

29
Q

describe what each part of a rotem describes…

A

R time = stimulation until beginning of clot formation. determined by clotting factors. if prolonged need FFP

K time = time for width of graph to reach a certain point and is a measure of time taken to reach a particular firmness of clot. determined by fibrinogen. hence if prolonged give cryoprecipitate

alpha angle = rate of clot formation. determined by fibrinogen. if low give cryoprecipitate

max amplitude (MA) - max extent of clot. determined by platelets. if low give platelets

LY30 - lysis at 30mins - measures clot breakdown. if high give TXA

30
Q

what is DIC? causes?

A

disseminated intravascular coagulopathy

widespread activation of clotting cascade
microclots and depletion of clotting factors so bleeding.

infection/ sepsis
trauma
malignancy
transfusion
placental abruption/ amniotic fluid embolism.

31
Q

what are the lab findings in DIC?

A

high APTT, PT , TT
low platelets
low fibrinogen
high d dimer

32
Q

define thrombocytosis and thrombocytopenia?

A

> 450

<150

33
Q

classify the cellular components of blood…

A
34
Q

Classify drugs that work on the thrombotic system..

A

Also mention TXA = which promotes thrombosis by blocking the conversion of plasminogen to plasmin and hence the breakdown of fibrinogen.

these are all active drugs - can also mention replacement of certain products (platelets, factors) to improve thrombosis

35
Q

Classify the antiplatelet drugs

A

Can be classified via mechanism.
Their mechanism works through inhibiting platelet activation and aggregation through various platelet receptors
most of these acts via Gi to activate platelets.

Activation
- P2Y12 receptor (ADP receptor) = clopidogrel, prasugrel, ticagrelor
- Thromboxane receptor = reduced thromboxan production via COX inhibitors.
- phosphodiesterase inhibitors = Dipyramiole (increases cAMP , opposite to Gi)

Aggregation and activation
- GPIIb/IIIa receptor = tirofiban

36
Q

Classify the anticoagulant drugs

A

can be divided into two broad groups - parental and oral

parenteral
- direct thrombin (F2a) inhibitors = Bivalirudin
- indirect thrombin inhibitors = unfractionated heparin, LMWH (enoxaparin, dalteparin), fondaparinux

oral anticoagulants
- coumarins = warfarin
- direct Xa (DOAC) = apixaban, edoxaban, rivaroxaban.
- direct thrombin (IIa) = dabigatran

37
Q

tell me about clopidogrel..

A

ADP receptor anatagonist works via inhibiting platelet activation through irreversible antagonism.

commonly used in high risk CVS events such as MIs and Strokes, stents or peripheral vascular disease to prevent further thrombosis and ischaemia.

75mg OD is usually given but often a loading dose of 300mg.

Pharmacodynamics:
- It reduces platelet activation and thus has some side effects related to this bleeding & bruising (type A reaction)
- it can also lead to thrombotic thrombocytopenia pupura - rare side effect where platelets form small clots throughout the body and platelet levels are depleted. (type B)

pharmacokinetics..
- It is taken orally and absorbed from GI tract
- mostly broken down by esterases but some converted to active form.
- prodrug and converted to active form by CYP450
- genetic polymorphisms - some people cant convert to prodrug v. well.
- omeprazole also inhibits this conversion
- 98% PB
- renal excretion.

38
Q

tell me about aspirin…

A

commonly used antiplatelet - irreversible COX inhibitor COX1 > COX2
used for pain, antiplatelet actions in prevention and treatment of MI, strokes, PVD and also for its antipyretic effects.

can be given PO, PR usually 75mg or 300mg loading dose in acute setting (has a quicker onset)

pharmacodynamics:
- COX inhibition results in less prostaglandins (pain and inflammation), less thromboxane (less platelet activation)
- thus side effects can be type A - bleeding, bruising, GI ulceration, renal dysfunction and worsening of asthma (leukotrienes)
- or type B - allergy, reyes disease in children

pharmacokinetics:
- absorbed from stomach and intestine
- pKa 3.5, acid. acidity of stomach promotes absorption.
- 80% PB
- converted to salicyclates in liver and GIT
- renal excretion.

39
Q

Tell me about dipyramidole?

A

Phosphodiesterase inhibitor
inhibits platelet activation

Main role is in stroke prevention and treatment. particularly when clopidogrel is contraindicated.

40
Q

what are the main uses of GPIIb/IIIa inhibitors?

A

tirofiban
IV infusion, very short half life
used for coronary stenting

41
Q

Tell me about unfractionated heparin

A

Heparin is an endogenous molecule normally produced by mast cells and works via binding ATIII to potentiate its inhibition of factor 2,10, 9.11 and 12.

It has now mostly been replaced by LMWH due to monitoring issues however still used in special circumstances e.g. acute limb ischaemia and vascular surgery.

given as IV infusion and requires close monitoring of APTT and platelet count.

Issues:
- type A - bleeding
- type B - hypotension with large IV bolus, hypersensitivity, osteoporosis, and heparin induced thrombocytopenia.

42
Q

can you tell me about heparin induced thrombocytopenia?

A

This comes in 2 forms
type 1 = non immune, mild, self resolves, no need to stop infusion. develops few days after.
type 2 = immune mediated - IgG antibodies to platelet factor 4 (PF4) which results in platelet activation and destruction which inturn causes strokes and bleeding. , severe and develops on day 5-10.

can be distinguished by timing, level of platelet drop and is there is thrombosis.

43
Q

do you know a reversal agent for heparin?

A

protamine sulphate.
heparin is very negatively charged and acidic and can be neutralised by protamine which is basic and positively charged.

44
Q

tell me about LMWH…

A

LMWH is a newer form of heparin which has been fractionated and hence smaller.
IT also binds and potentiates ATIII however due to its size is limited to actions only on 2a and 10a.

it has become popular due to its more predictable nature and thus doesnt need monitoring and its improved side effect profile.

given subcutaneously
and needs adjustments in obesity and renal failure.

its downfalls
- cant be reversed by protamine (or atleast only slightly)
- can be underdosed in obesity - factor Xa levels can be checked in those where underdosing may occur

45
Q

which anticoagulants can be used in pregnancy?

A

heparins because they dont cross placenta - although LMWH much more favoured in comparison to unfractionated due to monitoring and HITT

aspirin low dose can also be used and is used for pre-eclampsai

avoid warfarin - teratogenic
avoid DOACs

46
Q

Tell me about warfarin

A

Commonly used oral anticoagulant. although more recently, its role is being replaced by newer agents such as the DOACs.

It is a coumarin based molecule
Works via inhibition of Vitamin K epoxide reductase. This inhibition prevents the reduction of vitamin K such that it cannot be replenished for its use in carboxylation of clotting factor and hence their activation

It mostly affects the production of factors 10, 9, 7 and 2 but also protein C and S

It only affects the synthesis of new clotting facotrs and hence takes around 3-5 days to work and should be bridged by LMWH. Also this bridging is useful as initially the inhibition of protein C and S gives pro-coagulant effects

It is taken orally and titrated to the INR and the range of INR depends on indication e.g. AF is 2-3 whereas a mechanical valve is 3-4.

pharmacodynamics
- bleeding
- N&V & diarrhoea
- teratogenic

pharmacokinetics
- good oral absorption
-metabolised by CyP450 and subject to inducer/inhibitors.
- many DDI = plasma protien binding (NSAIDs, phenytoin), CYP450 inhibitors (erythromycin) inducers ( phenytoin, COCP)

47
Q

how is a bleeding patient who normally takes warfarin managed?

A

stop warfarin
high INR no bleed - oral vit K

bleeding, mild = vitamin K IV

major bleed = Prothrombin complex concentrate (beriplex) or FFP

48
Q

what DOACs do you know? when are these indivaated

A

apixaban, edoxaban, rivaroxaban

indicated in venous thrombosis e.g. P.E, DVTs, prophylaxis for AF

49
Q

which DOACs can be reversed?

A

Dabigatran = monoclonal Ab

rivaroxaban and apixaban = Andexanet alpha

50
Q

which drugs are fibrinolytics ?

A

these are drugs that promote breakdown of fibrin clot.

normally plasminogen –> plasmin. this step is activated by tissue plasminogen activator.
plasmin cleaves fibrin.

there are a number of drugs that mimic tPA including streptokinase, alteplase

51
Q

how does transexamic acid work?

A

anti-fibrinolytic agent
blocks conversion of plasminogen to plasmin to prevent breakdown of fibrin

aims to prevent/ help with haemorrhage

used in major trauma and traumatic brain injuries after CRASH 2 and 3 studies. also often used in orthopedic surgery.

52
Q

name of 2 models of haemostasis

A

The Classical (Cascade) Model of Hemostasis
* clotting cascade

The Cell-Based Model of Hemostasis
* newer model incorporates the role of cells (especially platelets and endothelial cells)

53
Q

previous Q on iron metabolism/ storage - how much iron, transferrin and ferritin in the body?

A

iron - around 3g (4g in male)

ferritin - males up to 400ng/ml
females 15-150ng/ml

transferrin - normal saturation of iron around 20-50%

54
Q

what are transferrin and ferritin ?

A

ferritin is the intracellular storage protein for iron. used as a marker of iron deficiency/ overload

transferrin is the mechanism for transport of iron in the blood.

55
Q

where is iron stored?

A

mostly in liver, bone marrow and spleen

56
Q

how is iron absorbed and recycled?

A

absorbed from duodenum and upper jejunum
absorbed as Fe2+ and enhanced by vit C
hepcidin is a protein made by the liver that inhibits absorption for regulation

old damaged RBC are engulfed by macrophages and the iron in them is recycled.

57
Q

what are the causes of iron deficiency anaemia?

A

excess loss
* menorrhagia, GI malignancy

insufficient production
* dietary - iron lack
* malabsorption - low stomach acid

58
Q

is blood loss always pathological?

A

no - mensturation, venepuncture e.g. for haemochromatosis

PHYSIOLOGY PRIMARY (17 decks)

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