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cardiovascular lectures > platelets & plasma & platelet biochemistry > Flashcards

platelets & plasma & platelet biochemistry Flashcards

1
Q

lifespan of platelets

A

7-10 days

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2
Q

structure of platelets

A

cytoplasmic, anucleate & discoid(lens shaped) cells -> they become spiculated with pseudopodia once activated

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3
Q

function of platelets

A

form a platelet plug along with clotting factors to achieve haemostasis (stop bleeding) and close up holes in vessels

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4
Q

how are platelets made

A

from fragments of cytoplasmic material derived from cells called megakaryocytes in the bone marrow

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5
Q

what modulates platelet production

A

thrombopoietin

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6
Q

can platelets repair themselves

A

no because they are spherical and anucleate - they don’t have a nucleus

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7
Q

what is normal number of platelets

A

140-400 x 109/l

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8
Q

what happens when you have platelet deficiency in blood

A

thrombocytopenia

causes excess bleeding because cant form clots

main risk is cerebral bleeding

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9
Q

what happens when you have too many platelets in blood

A

thrombocytosis

can lead to arterial & venous thrombosis, leading to an increased risk of heart attack + stroke

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10
Q

what is a blood vessels very first response to damage

A
  1. to constrict due to neural
    control + release of endothelin-1 (released by endothelia cells)
  2. this temporarily slows the flow of blood in the affected area.
  3. this construction presses opposed endothelial surfaces of the vessel together and this contact induces a stickiness capable of keeping them ‘glued’ together.
  4. permanent closure of the vessel by constriction & contact stickiness only occur in the very smaller vessels of the microcirculation
  5. the stopping of bleeding depends on two interdependent processes that occur in rapid succession:
    1) formation of a platelet plug (primary haemostasis)
    2) blood coagulation
    (secondary haemostasis)
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11
Q

define haemostasis

A

the process to prevent & stop bleeding
Split into primary and secondary

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12
Q

what is primary haemostasis

A

initial response to vascular injury

formation of a platelet plug

3 steps after vessel injury:

  1. platelet adhesion
  2. platelet activation
  3. platelet aggregation
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13
Q

what is secondary haemostasis

A

coagulation cascade

formation of a fibrin clot

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14
Q

what happens when a vessel is injured

A
  • endothelial wall becomes exposed
  • smooth muscle contracts to limit blood loss
  • mechanisms of contraction:
    -endothelin release
    -nervous stimulation
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15
Q

describe platelet adhesion in primary haemostasis

A
  1. subendothelial collagen becomes exposed
  2. platelets bind to collagen via vWF using their receptor GP1B on the platelet membrane
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16
Q

describe platelet activation in primary haemostasis

A
  1. once bound to the subendothelium, platelets change shape
  2. binding of platelets to collagen fibre wall triggers them to release alpha and electron dense granules from secretory vesicles via exocytosis
    Alpha:
    - vWF, Thromboxane A2, fibrinogen
    and fibrin-stabilizing factor
    Electron-dense:
    - ADP, Ca2+, Serotonin
  3. ADP acts on acts on the P2Y1 and P2Y12 receptors causing platelet amplification
  4. ATP binds to P2X1 which also causes platelet amplification
  5. thrombin binds to PAR1 and PAR4 receptors - inducing platelet activation and further thrombin release - positive feedback
  6. results in the platelet changing shape = PLATELET ACTIVATION
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17
Q

describe how platelets change shape in platelet activation

A

they go from a smooth discoid shape to a more spiculated (spiky) with pseudopodia

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18
Q

what is impact of new changed shape of platelet after platelet activation

A
  • increased SA of platelet
  • increased possibility of cell to cell interactions
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19
Q

what are the alpha dense granules

A
  • vWF
  • Thromboxane A2
  • fibrinogen
  • fibrin-stabilizing factor
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20
Q

what are the electron dense granules

A
  • ADP
  • Ca2+
    -serotonin
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21
Q

describe platelet aggregation in primary haemostasis

A

platelet activation causes an increase in the expression of glycoprotein IIb/IIIa
(GPIIb/IIIa) receptors on the platelets

which binds to FIBRINOGEN (from alpha
granules) enabling new platelets to bind to the old ones so lots of platelets bind together

this is a positive feedback mechanism called PLATELET AGGREGATION

allows formation of a weak platelet plug to temporarily protect from hemorrhage until further stabilization of fibrinogen to fibrin via thrombin occurs in secondary hemostasis.

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22
Q

what further stimulates platelet aggregation

A
  • platelet adhesion rapidly induces them to synthesise THROMBOXANE A2 (causes vasoconstriction & platelet activation)
  • this is released into the extracellular
    fluid and acts locally to further stimulate platelet aggregation and the release of there secretory vesicle contents
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23
Q

what is the effect of contraction on the effectiveness of a platelet plug

A
  • platelets contain a very high
    concentration of actin & myosin
  • This results in compression and strengthening of the platelet plug
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24
Q

what does vascular smooth muscle in the damaged vessel do during primary haemostasis

A
  • it is is simultaneously being stimulated to contract - decreasing blood flow to the area & pressure within the damaged vessel.
  • This vasoconstriction occurs as a result of platelet activation - due to the
    thromboxane A2 released and by the chemicals contained in the platelets secretory vesicles
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25
Q

why doesn’t the platelet plug expand away from the damaged
endothelium in both directions

A

the answer is 2 fold:

  • The normal undamaged endothelium either side of the damage begin to synthesise and release prostacyclin (also known as prostaglandin I2 (vasodilator) )which is a profound inhibitor of platelet aggregation
  • The normal endothelium also release nitric oxide, which is not only a vasodilator but also an inhibitor of platelet adhesion, activation & aggregation
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26
Q

what is the coagulation cascade

A

when a series of proteolytic enzymes (clotting factors) that circulate in an inactive state are activated (usually by exposure to tissue
factor) in a cascade or waterfall sequence - in order to generate the key enzyme THROMBIN which cleaves fibrinogen creating fibrin polymerisation i.e a blood
clot

TRANSFORMS BLOOD INTO A SOLID GEL - A CLOT OR THROMBUS

IT IS MAINLY MADE OF FIBRIN

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27
Q

why does clotting occur

A

to support & reinforce the platelet plug and to solidify blood that remains in the wound channel

it occurs locally around the platelet plug

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28
Q

is the coagulation cascade an all-or-nothing response

A

NO

has multiple steps which allow for biological amplification & allows for regulation

it can be graduated in response to severity of challenge

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29
Q

why is blood fluid inside vessels

A

the proteins of the coagulation cascade and the platelets circulate in an inactive
state

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30
Q

what activates proteins and platelets

A

tissue factor

this is present on every single cell APART from endothelial cells thus when endothelium is punctured etc.
blood comes into contact with tissue factor and thus starts clotting

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31
Q

what happens if blood clots inside vessel

A

thrombosis

32
Q

what happens if blood fails to clot outside vessel

A

bleeding disorder

33
Q

what proteins are there in the blood

A
  1. coagulation proteins/clotting factors (enzymes)
  2. plasma proteins
    • albumin
    • carrier proteins
    • immunoglobulins
34
Q

what does albumin do

A

most numerous protein in plasma

maintains oncotic pressure

35
Q

where is albumin produced

A

liver

36
Q

what are carrier proteins used for

A

to transport nutrients and hormones

37
Q

what are immunoglobulins

A

antibodies produced by plasma cells (differentiate B lymphocytes),

several classes;
- IgG (most important)
- IgM (all start off as this)
- IgA
- IgE (produced in response to non-self protein antigens)

38
Q

what does a lack of albumin result in

A

oedema, carries; fatty acids, steroids & thyroid
hormones

39
Q

what are all the coagulation proteins/ clotting factors

A

important factors:

  • IIa: Thrombin
  • Ia: Fibrin
  • XIIIa: Fibrin-stabilizing factor
  • IV: Ca2+

vitamin K-dependent factors - cannot be synthesized without vitamin K:
- X
- IX
- VII
- II

40
Q

function of clotting factors

A

to make blood clot

by converting
soluble fibrinogen into insoluble fibrin polymer

41
Q

what are the 2 pathways for a coagulation cascade

A

there are 2 parallel pathways

intrinsic -everything necessary
for it is within the blood

extrinsic - since a
cellular element outside the blood is needed

42
Q

what happens to the 2 parallel coagulation cascades under physiological conditions

A

the pathways are in fact not parallel but instead are activated sequentially with thrombin serving as the link between them

43
Q

explain the intrinsic pathway of the coagulation cascade

A
  1. The first plasma protein in the intrinsic pathway is called factor XII (12).
  2. It is activated into factor XIIa when it comes into contact with exposed collagen fibres underlying
    the damaged endothelium - this is known as contact activation and explains why blood clots outside the body e.g. in a test tube, since factor XII comes into contact with glass.
  3. Factor XIIa then catalyses the activation of factor XI to factor XIa
  4. Factor XIa then catalyses the activation of factor IX to factor IXa
  5. Factor IXa then catalyses the activation of factor X to factor Xa, NOTE; factor VIIIa also is involved in the conversion of factor X into factor Xa, factor VIIIa acts as a cofactor is this conversion with factor IXa to activate factor X
  6. Factor VIII is essential for clotting, in haemophilia A there is a lack of this clotting factor
  7. Factor Xa is the enzyme that converts prothrombin to thrombin - thrombin is the enzyme which then goes onto convert the soluble fibrinogen to the insoluble fibrin which can be used to secure the blood clot and build it up
44
Q

explain the extrinsic pathway of the coagulation cascade

A
  1. begins with a protein called tissue factor, which is not a plasma protein. It is located on the outer plasma membrane of various tissue cells, including fibroblasts and other cells in the walls of blood vessels OUTSIDE the endothelium
  2. Blood is exposed to subendothelial cells when vessel damage disrupts the
    endothelial lining
  3. tissue factor then binds a protein called factor VII which becomes activated to factor VIIa - the complex formed, made up of tissue factor and factor VIIa then go on to catalyse the activation of factor X into factor Xa.
  4. Additionally, this complex also catalyses the activation of factor IX, which can then help activate even more factor X by way of the intrinsic pathway
  5. Thus it can be seen that the clotting cascade can be initiated by either the
    activation of factor XII or the generation of the tissue factor - factor VIIa complex
    - NOTE: thrombin also contributes to the activation of; 1) factors XI & VIII in the intrinsic pathway 2) factor V, with factor Va then serving as a cofactor for factor Xa. Also thrombin also goes on to activate platelets too (mentioned above) - these are its positive feedback mechanisms

13

45
Q

what is the usual way of initiating clotting in the body

A

the extrinsic pathway

intrinsic plays a rare role

46
Q

why is thrombin initially only generated by extrinsic pathway

A

because the amount of
thrombin produced in this pathway is too little to produce adequate sustained coagulation.

BUT it is large enough to trigger thrombin’s positive feedback mechanisms on the intrinsic pathway - activation of factors V,VIII & XI and the
activation of platelets. This is all that is needed to trigger the intrinsic pathway
independently of tissue factor XII. This pathway then generates the large amounts of thrombin required for adequate coagulation.

47
Q

role of liver in clotting

A
  1. is the site of production for many of the plasma clotting factors
  2. produces bile salts which are essential for the absorption of the lipid-
    soluble substance vitamin K. The liver requires vitamin K to produce prothrombin and several other clotting factors
48
Q

what is fibrinolysis

A

a process that prevents blood clots from growing and becoming problematic.

a fibrin clot is not designed to last forever, it is a
temporary fix until permanent repair of the vessel occurs:
- Plasminogen is converted by plasminogen activators into plasmin which then goes
on to break fibrin down and thus the entire blood clot

49
Q

what is thrombosis

A

formation of clot (thrombus) inside blood vessel

50
Q

what receptor is on surface of plaetelets

A

glycoprotein IIb/IIIa

51
Q

what is plasma

A

the translucent liquid component of blood that holds the cellular components of blood in suspension

52
Q

components of plasma

A

water

proteins

electrolytes, hormones, gases, nutrients & waste products

53
Q

what is serum

A

blood plasma without the clotting factors

54
Q

how much of plasma is water

A

91.5%

55
Q

how much of plasma is proteins

A

7%

56
Q

where are fibrin degradation products relevant

A

they are are clinically relevant in PE and DVT - D-Dimer

57
Q

inheritance of haemophilia

A

recessive X linked

only affects males because the gene that causes it is on X chromosome

females are carriers

58
Q

what causes haemophilia

A

genetic disorder

two types - a and b

not enough clotting factors in blood so
- slow clotting time
or
- long prothrombin time
‘
blood does not clot properly

can lead to spontaneous bleeding as well as bleeding following injuries or surgery

bleeding into muscles and joints

59
Q

what causes haemophilia a

A

deficiency of clotting factor VIII (8)

60
Q

how to treat haemophilia a

A

with factor VIII (8)

61
Q

what causes haemophilia b

A

deficiency of clotting factor XI (9)

62
Q

how to treat haemophilia b

A

with factor XI

63
Q

why is haemophilia b less common than a

A

the gene is smaller

64
Q

inheritance of von willerbrands disease (VWD)

A

autosomal dominant
affects ALL generations
affects males and females
can get male to male transmission

65
Q

what causes VWD

A

fault in the gene involved in the production of von Willebrand factor.

VWF is required for platelets to bind to damaged blood vessels, so lack of VWF =
platelet dysfunction, hence muco-cutaneous bleeding

is usually a mild bleeding disorder

characterised by muco-cutaneous bleeding:

66
Q

what is muco-cutaneous bleeding:

A

bleeding in skin & mucous membranes e.g. easy
bruising, prolonged bleeding from cuts, nose bleeds (epistaxis), spontaneous gum
bleeding/GI loss etc.

67
Q

is VWD common

A

yes
incidence up to 1%
often unrecognised & undiagnosed

68
Q

what are acquired bleeding disorders

A

have a recent onset
no family history
not lifelong

may be generalised or local bleeding

69
Q

most common cause of acquired bleeding conditions

A

anti-platelet or anti-coagulation medication

70
Q

less common causes of acquired bleeding conditions

A
  • liver disease
  • vitamin K deficiency
  • drugs
  • disseminated intravascular coagulation (DIC)
71
Q

how does liver disease cause acquired bleeding conditions

A

liver is the site of synthesis of coagulation actors and fibrinogen

liver disease is often associated with bleeding and prolonged prothrombin time (PTT)

most common cause of liver disease in alcohol

72
Q

how does vitamin K deficiency cause acquired bleeding conditions

A

vitamin K is needed for synthesis of coagulation factors :

II, VII, XI & X (2, 7, 9 & 10) - 1972

Vitamin K is a fat soluble vitamin

Deficiency is caused by malabsorption - especially in obstructive jaundice

Manifests as prolonged PTT

Treat with IV Vit K

  • With deficiency coagulation factors are still produced but they do not work
  • Newborns are vitamin K deficient, given it at birth
73
Q

how do drugs cause acquired bleeding conditions

A

aspirin - affects platelet function

heparin & warfarin ( (most widely used oral anticoagulant - works by inhibiting
vitamin K)) - affect coagulation cascade

steroids - make tissues thin and cause bruising and bleeding

74
Q

what is disseminated intravascular coagulation (DIC)

A

DIC is is a serious disorder in which the proteins that control blood clotting become overactive.

Activation of the coagulation cascade inside blood vessels, thrombin is produced, causing fibrinogen > fibrin, form microvascular thrombosis’(platelet plugs) everywhere e.g. in organs etc.

  • Results in the deficiency of clotting factors & platelets since they’ve been used up in the formation of the micro-vascular thrombosis’ - doctors think its a blood condition causing deficiency but its because of the micro-vascular thrombosis

not very common

75
Q

causes of DIC

A

1) sepsis
2) obstetric (anything that goes wrong with pregnancies e.g. dead
foetus + pre-eclampsia )
3) malignancy

76
Q

treatment of DIC

A

treat underlying cause and stop generations of intravascular
thrombin then transfuse new platelets etc.

cardiovascular lectures (15 decks)

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