Haemostasis Flashcards

1
Q

What is haemostasis?

A

process whereby haemorrhage (bleeding) following vascular injury is arrested.

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2
Q

What does haemostasis depend on?

A

 blood vessel wall,
 circulating platelets
 coagulation factors

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3
Q

How does an intact cell wall prevent haemostasis through endothelial cells?(4)

A

 Prostacyclin: - this causes vasodilation and inhibits platelet aggregation

 Antithrombin & Protein C activator: - both inhibit coagulation

 Tissue plasminogen activator: activates fibrinolysis

 Von Willebrand
factor (vWF), which can bind platelets

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4
Q

What are the membrane receptors found in the membrane of platelets?

A

 GPIa/IIb complex & GPVI which are receptors for collagen

 Glycoproteins (GPIb & IIb/IIIa allows attachment of platelets to vWF, then to endothelium.

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5
Q

What is vasoconstriction?

A

 Immediate vasoconstriction of the injured vessel and reflex constriction of adjacent small arteries and arterioles - responsible for an initial slowing of blood flow to the area of injury

 reduced blood flow allows contact activation of platelets and coagulation factors

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6
Q

Describe platelet plug formation

A
  1. subendothelial collagen is exposed.
  2. von Willebrand Factor (vWF) is released causing the platelets to change form and adhere to the subendothelial collagen via GPIa/IIb.
  3. which activates it.
  4. platelets change their shape from a disc to a more rounded form and they release the contents of their granules (platelet release reaction),
  5. the most important content of which is ADP. The platelets are also stimulated to produce the prostaglandin, thromboxane A 2 , from arachidonic acid derived from the cell membrane.
  6. The release of ADP and thromboxane A 2 causes an interaction of other platelets with the adherent platelets and with each other (secondary platelet aggregation), thus leading to the formation of a platelet plug
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7
Q

Describe the coagulation cascade(5)

Extrinsic pathway

A
  1. Coagulation begins when tissue factor activated on the surface of injured cells binds and activate factor VII
  2. Recruitment of other clotting factors and activation of platelets (amplification). Factor 7 activates Factor 10 which turns prothrombin to thrombin
  3. Huge burst of thrombin from activated platelets change fibrinogen into fibrin (propagation).
  4. Intrinsic pathway activated by tissue damage and extrinsic pathway activated by surface contact.
  5. Each reaction requires phospholipid and specific co-factors, and calcium to bind them.
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8
Q

How is coagulation regulated? (3)

A

 Anti-thrombin - an important inhibitor of terminal proteins of cascade especially FXa and thrombin (Heparin potentiates its action markedly)

  1. Protein C and S.- Protein C is vit K-dependent and inactivates the cofactors of Va and VIIIa, and stimulates fibrinolysis. Protein S acts as cofactor for C.
  2. Tissue Factor pathway inhibitor (TFPI) - inactivates factor Xa and then the TFPI/FXa complex inhibits FVIIa
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9
Q

What is fibrinolysis?(3)

A

 Fibrinolysis (like coagulation) is a normal haemostatic response to vascular injury.
 is the enzymatic breakdown of fibrin in blood clots
 fibrin is degraded by plasmin

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10
Q

Describe the steps of fibrinolysis

A
  1. Plasminogen (precursor) is activated by tissue plasminogen activator (t-PA).
  2. Produces plasmin, an enzyme which metabolises clots.
  3. Fibrin degradation products (FDP), such as D dimers from the degradation of cross-linked fibrin, are produced.
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11
Q

What is thrombosis?(3)

A

 the pathological process whereby platelets and fibrin interact with the vessel wall to form a haemostatic plug to cause vascular obstruction
 may be arterial, causing ischaemia
 or venous, leading to stasis

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12
Q

What can thrombosis lead to?(4)

A

underlies ischaemic heart, cerebrovascular and peripheral vascular diseases, venous occlusion and pulmonary embolism.

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13
Q

How can defective haemostasis arise?(3)

A

 A vascular disorder
 Thrombocytopenia or a disorder of platelet function
 Defective blood coagulation

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14
Q

Summarise the screening tests

A

 Prothrombin Time (PT)
 Activated Partial Thromboplastin Time (APTT)
 Thrombin (clotting) time (TT)

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15
Q

What is Prothrombin Time (PT) ?(2)

A

 measures factors VII, X, V, prothrombin (II) and fibrinogen
 Tissue thromboplastin (a brain extract) or [synthetic] tissue factor with lipids and calcium is added to citrated plasma

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16
Q

What is Activated Partial Thromboplastin Time (APTT)?(2)

A

 Measures factors VIII, IX, XI and XII in addition to factors X, V, prothrombin (II) and fibrinogen.

 Three substances – phospholipid, a surface activator (e.g. kaolin) and calcium are added to citrated plasma

17
Q

What is Thrombin (clotting) time (TT)?(2)

A

 sensitive to a deficiency of fibrinogen or inhibition of thrombin
 adding thrombin to plasma and measuring the time taken to clot, which is prolonged when there is an inherited or acquired deficiency of fibrinogen, or an inherited or acquired abnormal fibrinogen molecule luted bovine thrombin is added to citrated plasma

18
Q

What us fibrinogen quantitation?

A

Measures fibrinogen deficiency

19
Q

What is DIC?

A

disseminated intravascular coagulation

20
Q

What is FDP?

A

• Fibrin degradation products (FDPs), also known as fibrin split products, are components of the blood produced by clot degeneration. Clotting, also called coagulation, at the wound site produces a mass of fibrin

21
Q

What are the principles of clotting?(5)

A
	Incubate plasma with reagents necessary for coagulation
	Phospholipid, co-factors
	Trigger or activator
	Calcium
	Measure time taken to form fibrin clot
22
Q

VWF synthesis and storage

A

Synthesis
→Endothelial cells contain Weibel Palade bodies

→Megakaryocytes
→Platelet a granules

→Plasma VWF entirely derived from endothelial cells

23
Q

Distribution of VWF

A

→Constitutive path (95%)
→Regulated path (5%)
→Weibel-Palade bodies (storage granules of endothelial cells)

24
Q

describe Initiation of coagulation

A

The TF leads to the production of a small local amount of thrombin, which is the initiation step of the coagulation process

25
Q

what do activated platelets present?

A

→negatively-charged phospholipid membrane at the site of the injury
→on which the process of coagulation (secondary haemostasis) can occur, if needed

26
Q

how does a tissue factor drive coagulation?

A

→TF is outside the lumen
→Formation of TF-FVIIa complex
→ Recruitment of FX and formation of thrombin

27
Q

what happens after FVII is activated?

A

→the complex binds small amounts of FX and FV to the exposed endothelial surface,

→ produce small quantities of thrombin

28
Q

what do the activated factors (among them FVIII and FIX) enable the binding of ?

A

enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process

29
Q

what are the key players in fibrinolysis?

A

→Plasminogen
→ Tissue plasminogen activator (t-PA) & urokinase (u-PA) →Plasminogen activator inhibitor -1 and -2 α2-plasmin inhibitor

30
Q

what do the activated factors (among them FVIII and FIX) enable the binding of ?

A

→enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process

31
Q

what are the simplified steps of haemostasis?

A
→Tissue injury
→Vasoconstriction
→Platelet activation
→Haemostatic plug
→Coagulation
→Stable clot formation
→Clot dissolution
32
Q

Primary haemostasis:

A

→Vasoconstriction (immediate)
→Platelet adhesion (within seconds)
→Platelet aggregation and contraction (within minutes)

33
Q

Secondary haemostasis:

A

→Activation of coagulation factors (within seconds) →Formation of fibrin (within minutes)

34
Q

Intrinsic pathway:

A
  1. Factor 12 is activated by prekallikrein
  2. 12a activates 11
  3. 11a activates 9
  4. Factor 10 activates converts Prothrombin to thrombin
  5. Thrombin turns fibrinogen to fibrin