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Year 3 - Clinical Science and Professionalism > Haemostasis 1 > Flashcards

Haemostasis 1 Flashcards

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1
Q

what type of feedback system is blood coagulation

A

Positive feedback

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2
Q

Define haemostatsis

A

Haemostatsis is defined as the cessation of bleeding at a vascular injury site via the formation of a thrombus

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3
Q

what is the two primary components of a thrombus

A
  • platelet plug

- fibrin clot

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4
Q

what is the difference between primary and secondary haemostatsis

A
  • primary haemostatsis is the platelet plug

- secondary haemostats is the fibrin clot

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5
Q

describe what a fibrin clot is

A
  • activation of coagulation factor proteases results in a protease thrombin
  • thrombin is essential for the production of fibrin monomers
  • these are cross linked and form a meshwork around the platelet plug
  • this is termed secondary haemostasis
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6
Q

Describe the structure of platelets

A
  • NOT CELLS, little bags of cytoplasm shed from megakaryocytic
  • no nuclei
  • 1-4um in diameter
  • each megakaryocyte can produce over 1000 platelets
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7
Q

how long can platelets survive for

A
  • there are about 1-2 platelets per 20 RBC

- survive 8.5-10 days and have a half life of 4 days

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8
Q

what regulates platelet production

A
  • Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced in the kidneys and liver.
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9
Q

Describe how the platelet plug forms (primary haemostasis)

A
  • damaged endothelium
  • this means that collagen underneath the endothelium is exposed to the blood
  • Von willebrand factor (VWF) binds to the exposed collagen
  • platelets then bind to the VWF via the platelet GP1b receptors (platelets can also bind directly to the collagen via Gp1a and Gp6 receptors but this is very weak)
  • the VWF has formed a bridge between the collagen and platelets, this is called platelet adherence
  • the adherent platelets express the GP2b/3a receptor
  • GP2b/3a receptors bind to fibrinogen which binds more platelets to form a meshwork this is called platelet aggregation
  • the binding of platelets cause the platelets to become activated
  • they change shape and become spiky and entailed together
  • they release ADP and thromboxane A2 (TXA2) and serotonin (5-HT) from granules, this is called the platelet release reaction
  • ADP & TXA2 attract more platelets to the site which aggregate to form a platelet plug.
  • 5-HT acts on local smooth muscle to increases local vasoconstriction.
  • The spiky platelets in turn release cytokines which attract even more platelets and so a positive feedback system operates until a plug large enough to stop the bleeding is formed.
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10
Q

what normally prevents platelet adhesion

A
  • the endothelium which is intact continuously releases nitric oxide and prostacyclin (PG12) this prevents platelet adhesion
  • this also happens adjacent to the damage endothelium to prevent the platelet plug from separating
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11
Q

what is van willebrand factor

A
  • it is a glycoprotein that circulates in the blood and binds to the exposed collagen
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12
Q

what receptors do the platelets bind to when creating the platelet plug

A
  • platelets then bind to the VWF via platelet GP1b receptors.
  • Platelets can also bind directly to collagen via Gp1a and Gp6 receptors: However without VWF the binding is very weak and the platelets are easily dislodged).
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13
Q

what is platelet adherence

A
  • when the platelets bind to the VWF via platelet GP1b receptors
  • this means that the VWF has formed a bridge between the collagen and platelets this is called platelet adherence
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14
Q

where is Von williebrand factor stored

A

stored in the endothelial cells, inside granules called Weibel–Palade bodies (WPBs)

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15
Q

what substances are released in the platelet release reaction

A
  • They release adenosine diphosphate (ADP), thromboxane A2 (TXA2) and serotonin (5-HT) from granules
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16
Q

what does ADP and TXA2 do in the platelet plug

A
  • ADP & TXA2 attract more platelets to the site which aggregate to form a platelet plug.
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17
Q

what does 5HT do in the platelet plug

A

5-HT acts on local smooth muscle to increases local vasoconstriction which reduces the local blood flow

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18
Q

where is VWF made

A

liver

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19
Q

what determines the bleeding time

A
  • the formation of the platelet plug determines the bleeding time
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20
Q

how long does it take for bleeding to stop

A

normally stops within 1-9 minutes but may be longer in children (1-13 minutes) and tends to take slightly longer in females than in males

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21
Q

what does the bleeding time test involve (test for platelet function)

A
  • A lancet or scalpel blade is used to make a shallow incision 1 millimeter deep on the underside of the forearm.
  • The time from when the incision is made until all bleeding has stopped is measured and is called the bleeding time
  • Normal values fall between 3 – 10 minutes.
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22
Q

what are the three pathways in the fibrin clot

A
  • extrinsic pathway
  • intrinsic pathway
  • common pathway
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23
Q

Describe the steps in the extrinsic pathway

A
  • Factor VII is exposed to tissue factor (III) when the blood vessel is injured
  • the tissue factor (III) converts factor VII to VIIa
  • VIIa then reacts with calcium and factor X in the blood to form factor Xa
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24
Q

what is the clinical test for extrinsic and common pathway

A

PT

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25
Q

what type of protein is factor VII

A

plasma protein

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26
Q

where is tissue factor (III) found

A
  • it is intracellular in the endothelium and smooth muscle
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27
Q

what are the substances called that convert factor X to Xa called

A

The enzymes and calcium which convert factor X to Xa are sometimes called the tenase complex

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28
Q

Describe the steps of the common pathway

A
  • Xa and calcium from the extrinsic pathway cause prothrombin to be converted to thrombin
  • thrombin turns fibrinogen to fibrin
  • thrombin also creates a bit of XIII
  • XIII turns into XIIIa
  • XIIIa stabilises the fibrin into a stable clot
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29
Q

What causes amplification of thrombin formation

A
  • the extrinsic pathway produces a small amount of thrombin by forming a small amount of Xa
  • The initially formed thrombin converts three other factors – V VIII, XI into their active forms Va VIIIa Xia
  • Xia then converts factor IX to IXa
  • VIIIA and Isa increases conversion of X to Xa
  • Va increases effective of the increased Xa
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30
Q

Describe the steps of the intrinsic factor

A
  • Factor XII is converted into XIIa
  • XI is converted to XIa by XIIa
  • IX is converted into Isa by XIa and calcium
  • then IXa and calcium is used to convert X to Xa
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31
Q

when is the intrinsic factor activated

A
  • it activates clotting when the blood is stagnant

- often happens in the atria or leg veins (deep vein thrombosis)

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32
Q

what is the clinical test for the intrinsic pathway and common pathway

A

is APPT (activated partial prothrombin time) – sometimes called surface activation pathway, the surface of the slide which is polar activates this surface

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33
Q

what test is used for assessing platelet function

A

bleeding time

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34
Q

What is the INR

A
  • number derived from the prothrombin time
  • it is used to assess the coagulability of blood in patients taking warfarin or heparin as they are at risk of abnormal clot formation such as deep vein thrombosis or pulmonary emboli
35
Q

What is the ideal INR value

A
  • in patients on warfarin or heparin 2-3 (not more than 3) is aimed for
  • INR healthy range is 0.8-1.2
36
Q

what are two types of haemophilia

A

Haemophilia A

Haemophillia B

37
Q

what is the difference between haemophilia A and haemophilia B

A
  • Hameophilia A is caused by a deficiency of factor VIII. It reduces the effectiveness of the positive feedback loop forming thrombin
  • Haemophilla B is caused by a deficiency of factor IX
38
Q

What are the two substances involved in getting rid of clots

A
  • antithrombin III

- plasmin

39
Q

Describe how clots are removed

A
  • Plasmin circulates in the blood in the form of an inactive precursor plasminogen. Plasminogen binds to platelet plugs as they form, and gets incorporated into the final clot. Plasminogen is held in its inactive form by alpha-2 antiplasmin which circulates in high concentration in the plasma
  • When the tissue is healed the plasminogen becomes plasmin this happens by tissue plasminogen activator (tPA)
  • this causes fibrinogen to be proteolysis and turned to fibrin
40
Q

what type of protein is antithrombin III

A
  • plasma protein
41
Q

what is the dominant form of antithrombin found in the blood plasma

A

α-antithrombin is the dominant form of antithrombin found in blood plasma.

42
Q

what does tPA do

A
  • Tissue plasminogen activator (tPA) is released from normal endothelial cells. It catalyses conversion of plasminogen to plasmin
  • One of its functions is to prevent a clot extending too far along a blood vessel into healthy tissue.
43
Q

name a product of fibrin breakdown

A

D-dimer

44
Q

why is D dimer important

A

Measurement of D-Dimer levels is an important test performed in patients with suspected thrombotic disorders (eg DVT).
- it is an indication that thrombosis is not present

45
Q

what other factors also catalyse plasminogen to plasmin

A

urokinase plasminogen activator, kallikrein, and factor XIIa

46
Q

what factors is vitamin K important for

A

requires for full effectiveness of Factors VII, IX and X of the coagulation cascade.

47
Q

what does vitamin K do

A

Vitamin K modifies the proteins to allow them to bind calcium ions.

48
Q

what are the two main forms of vitamin K

A

Vitamin K1 and vitamin K2.

49
Q

where are two main forms of vitamin K found

A
  • Vitamin K1 is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis.
  • Animals can convert it to vitamin K2.
  • Bacteria in the gut flora can also convert K1 into vitamin K2
50
Q

what are the risk factors for vitamin K deficiency

A
  • Liver disease,
  • poor diet (no green vegetables)
  • poor absorption, antibiotics
  • Deficiency of vitamin K seen as increased INR and may result in unstable clots. It may also be a factor in osteoporosis
51
Q

what is used in treatment for overdose of the anticoagulant drug warfarin and rat poisoning

A

Vitamin K

52
Q

what are the two classic anticoagulants

A

heparin

warfarin

53
Q

how is heparin given

A

Must be given parenterally (i.v. or subcutaneous) as not absorbed through gut

Short half-life (one hour) so give continuously or regularly

Effective instantly

54
Q

what does heparin do

A

Heparin binds to and massively increases the activity of anti-thrombin
Activated AT inhibits thrombin and factor Xa

55
Q

what does warfarin effect

A
  • Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors especially Factors VII, IX and X.
  • It also competes with sites on these factors that bind vitamin K reducing their effectiveness
56
Q

name the modern anticoagulants

A

Direct acting anticoagulatns DOACs

57
Q

name some direct acting anticoagulants DOACs

A
  • These agents include a direct thrombin inhibitor(dabigatran)
  • factor Xa inhibitors (eg rivaroxaban, apixaban and edoxaban).
58
Q

describe the positives and negatives for DOACs

A

Positives

  • less serious side effects than traditional anticoagulants
  • a rapid onset action and relatively short half-lives, therefore more effective
  • don’t need monitoring like warfarin

negative

  • more expensive and needed for kidney problem patients
  • is no antidote for the factor Xa inhibitors, so it is difficult to stop their effects in the body in cases of emergency
59
Q

Types of VWF disease

A
  • Autosomal inheritance – effects boys and girls the same
  • Type 1 – mild to moderate deficiency
  • Type 2 – protein present but defective
  • Type 3 – total absent of protein

Investigations show a prolonged bleeding time

60
Q

Treatment of VWF

A
  • Tranexamic acid which prevents plasminogen converting to plasmin - used in mild bleeding
  • Desmopressin (DDAVP) – raises levels of vWF by inducing release of vWF from weibelpalade bodies in endothelial cells
  • Factor VIII concentrate
61
Q

describe tissue factor III

A

Present on subendothelial tissue

  • Expressed by cells which are normally not exposed to flowing blood
  • Physical injury exposes TF to flowing blood
  • Necessary for the initiation of coagulation via factor VII
  • Massive trauma = massive tissue factor release
62
Q

Whats the treatment for severe haemophilia

A
  • Bleeds in soft tissues, joints, psoas, intracranial, operative sites, haematomas may become compromising
63
Q

what is the treatment of severe haemophilia

A
  • Learn to self administer factor concentrate
  • Moderate FVIII levels
  • Targeted – around activity

Haemophilia B
- treated with recombinant factor IX

64
Q

what is the treatment for mild and moderate haemophilia

A
  • Still need treatment consideration DDAVP for mild haemophilia A
  • Factor concentrate – often cannot self administer

Haemophilia B
- treated with recombinant factor IX

65
Q

Describe Antithrombin

A
  • Major inhibitor of thrombin and Xa
  • Also inhibits VII, IX, XI
  • Member of the serine protease inhibitor family
  • Inhibitory activity increased 5-10,000 fold in the presence of heparin
  • Physiologically binds to heparan sulphate on the surface of the vascular endothelium
66
Q

describe protein C and S

A
  • Vitamin K dependent glycoprotein sytnehsised in the liver
  • Help control the rate of blood clot formation

Protein C

  • Activated by thrombin – APC (Activated protein C)
  • Activation increased – 20,000 fold with thrombomodulin
  • Activated protein C – serien protease, inactivates Va and VIIIa

Protein S
- Cofactor for activated protein C (APC)

67
Q

what is the lifespan of a platelet

A
  • 8 to 14 days
68
Q

what system removes platelets from the blood

A
  • Removed from the circulation by the reticuloendothelial system
69
Q

describe what the cell membrane of a platelet it like

A
  • glycoproteins molecules have receptors for agonist, adhesive, coagulation factors and other platelets
  • the receptors that are most abundant are GPIIb/IIIa and Gp1b
  • the cell membrane also contains phospholipids
  • it is associated with prostaglandin synthesis, calcium mobilisation, localisation of coagulant activity to the platelet surface
70
Q

what are the organelles in a platelet

A
  • there are platelet specific granules such as
  • dense osmophilic granules (dense bodies, d-granules)
  • a granules are the glue that hold the platelets together
71
Q

what are the substances that can be in a-granules

A
  • VWF
  • platelet factor 4
  • b-thromboglobulin,
  • thrombospondin,
    factor V,
    fibrinogen,
    fibronectin,
    platelet derived growth factor
    high molecular weight
    kininogen,
    tissue plasminogen activator inhibitor-1
72
Q

what acid does VWF release when it binds to IIb

A

arachidonic acid

73
Q

describes what happens to the arachidonic acid released when VWF binds to IIb

A
  • Arachidonic acid is released converted to by lipo-oxygenase enzymes to leucotrienes – chemoattractants to white cells, remaining Arachidonic Acid converted by cyclooxygenase and then TXA synthetase into Thrombocxane.
  • Thromboxane causes further granule release and local vasoconstriction and further local aggregation – exerts this by intracellular calcium shifts.
74
Q

name some serious inherited platelet disorders

A
  • Lack GpIb – Bernard Soulier syndrome – have thrombocytopenia as well
  • Lack GpIIb/IIIa – Glanzmann’s – all the clotting tests look normal except the fact that the platlets don’t work
  • Likely to need platelets or Novoseven medication that is a turbo boost to the clotting system that try’s to get some thrombin activity
75
Q

what is the disorder called when you lack Gp1b

A

– Bernard Soulier syndrome

76
Q

What is the disorder called when you lack GpIIb/IIIa

A

Glanzmann’s – all the clotting tests look normal except the fact that the platlets don’t work

77
Q

what are the less serious platelet conditions

A
  • Storage pool disorders

* Weak agonist response defects

78
Q

what is the most common inherited blood clotting disorder

A

von willebrand disease

79
Q

what protein family is antithrombin a part of

A

Member of the SERine Protease INhibitor family

80
Q

what increases the action of antithrombin

A
  • Inhibitory activity increased 5 -10,000 fold in the presence of heparin
  • Physiologically binds to heparan sulphate on the surface of the vascular endothelium
81
Q

what are the vitamin K dependent glycoproteins synthesised in the liver

A

Protein C and Protein S

82
Q

how is protein C activated

A
  • it is activate by thrombin

- the activation is increased 20,000 fold with thrombomodulin

83
Q

what do protein C and S do

A

proteins C and S help adjust the rate of blood clot formation.

84
Q

What would you find in investigations in haemophilia A

A
  • Increase in APTT

- Decreased factor VIII

Year 3 - Clinical Science and Professionalism (32 decks)

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