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Blood cells- OB/Biochem > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

haemostasis definition

A

A process to prevent and stop bleeding, meaning to keep the blood within in a damaged blood vessel

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2
Q

What is the opposite of haemostasis?

A

haemorrhage

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3
Q

Three major steps of haemostasis

A

vasoconstriction- vasospasm- smooth muscle in blood vessels constricts

temporary blockage of a break by a platelet plug- platelets stick together to form a temporary seal in the vessel wall

blood coagulation or formation of a fibrin clot- reinforces the platelet plug with fibrin threads that act as a molecular glue

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4
Q

Explain the vasospasm stage

A

smooth muscle cells are controlled by vascular endothelium, which releases intravascular signals to control contraction

local sympathetic pain receptors recognise a damaged blood vessel

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5
Q

How were all stages proved to be important?

A

arterial constriction- control of bleeding in an anti coagulated rabbit

platelet plug formation- thrombocytopenia, platelet count less than 10,000

fibrin filament assembly- haemophilia, lack of factor XIII or IX

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6
Q

What are platelets?

A

A component of blood, whose function is to react to bleeding from blood vessels by clumping, initiating blood clot formation.

Fragments of cytoplasm that are derived from megakaryocytes of bone marrow

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7
Q

life span of platelets in plasma

A

8-10 days

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8
Q

concentration of platelets in blood

A

4x10^8 per ml

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9
Q

three stages of platelet plug formation

A

adhesion, aggregation, activation

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10
Q

Explain adhesion

A
  1. when endothelial layer of vessels is disrupted, collagen and von Willebrand factor are exposed
  2. the platelet GP1b-IX-V receptor binds with VWF
  3. GPVI receptor and intern a2B1 bind with collagen

platelets bind to the endothelial cells and sub endothelial tissues

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11
Q

Explain aggregation

A
  1. The binding of the platelets to the endothelium activates the GPIIb/IIa receptors, allowing them to bind with vWF or fibrinogen
  2. fibrinogen is a rod like protein capable of binding GPIIb/IIa at both ends, which allows the proteins to aggregate
  3. binding to vWF on the endothelium helps stabilise the complex
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12
Q

What is GBIIb/IIa?

A

Glycoprotein that forms an integral complex found on platelets

It forms a receptor for fibrinogen and vWF, aiding platelet activation

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13
Q

Explain the activation of aggregation

A
  1. collagen from the sub endothelium binds with receptors GPVI and intern a2B1 on the platelet
  2. granules then secrete ADP and TXA2- thromboxane A2- via the canalicular system
  3. the aggregation mediators bind to the receptors on the platelet surface, resulting in an increase in intracellular calcium via Gq activation which activates PKC, in turn activating phospholipase A, which manipulate the cytoskeletal elements
  4. this calcium triggers the calcium-dependent association of the glycoprotein integrin complex GPIIb/IIa which is able to bind to fibrinogen, resulting in the platelets sticking together forming a clot
  5. thromboxane A2 reduces prostacyclins
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14
Q

How can activation of platelets be visualised?

A

Use scanning electron miscopy to view the different structures of the microtubule/actin filament complex to show early dendritic, early spread and spread conformations

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15
Q

how is platelet activation inhibited?

A

intact endothelial lining secretes nitric oxide, endothelial ADPase and prostacyclin

prostacyclin bind to prostanoid receptors on the surface of resting platelets, stimulating Gs to produce adenyl cyclase, increasing cAMP, which activates the cAMP activated calcium pump, promoting the efflux of calcium

ADPase degrades ADP

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16
Q

ADP function

A

binds to purinergic receptors on the platelet surface P2Y12 which is coupled to Gi

reduces adenylate cyclase activity, and lowers cAMP concentrations

also binds to P2Y1 Gq receptor, increasing IP3, more intracellular release of calcium

more calcium inside- activates GPIIb/IIa

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17
Q

what granules contain ADP?

A

delta

18
Q

What do platelet defects cause?

A

bruising- haemorrhage

19
Q

What is this organisation of platelets called?

A

primary plug

20
Q

What else do the platelets secrete + function?

A

5-HT

when platelets bind to a clot they release serotonin, which acts as a vasoconstrictor, causing endothelial smooth muscle to contract directly

potentiate the effects of other vasoconstrictors- angiotensin II or norepinephrine

21
Q

What is the secondary stage of haemostasis?

A

coagulation cascade- Formation of fibrin, which follows two paths

22
Q

what are the two paths?

A

intrinsic- contact activation pathway

extrinsic- tissue factor pathway

23
Q

What is thrombin + how is it formed?

A

Thrombin, blood coagulation factor IIa, acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin

produced by the enzymatic cleavage of two sites on prothrombin

glutamate becomes carboxylated catalysed by vitamin K dependent enzyme

prothrombin binds to calcium binds to platelet phospholipid

colocalisation with actors Xa and Va

24
Q

What happens to fibrin?

A

thrombin also converts factor XIII into XIIIa, which is a transglutaminase

it catalyses the formation of covalent bonds between lysine and glutamine residues in fibrin

covalent bonds increase the stability of the fibrin clot

25
Q

explain extrinsic pathway

A
  1. following damage to blood vessel, FVII leaves the circulation and comes into contact with tissue factor
  2. the tissue factor FVIIa complex activates FIX and FX
  3. FXa and cofactor Fva form the prothrombinase complex which activates prothrombin to thrombin
  4. thrombin activates other components of the coagulation cascade, including FV and FVIII, releasing it from bound vWF
  5. Factor XIa activates free factor IX on the surface of activated platelets
  6. Factor IX and VIIIa form the tens complex, which activates more Factor X, producing more factor Va
26
Q

What produces the tissue factor?

A

expressed by cells which are normally not exposed to flowing blood, such as sub endothelial cells like smooth muscle cells and cells surrounding blood vessels such as fibroblasts

they are membrane bound proteins

27
Q

Explain intrinsic pathway

A
  1. primary complex on collagen by high molecular weihjt kininogen HMWK, prekallikrein and Hageman factor is formed
  2. Prekallikrein is converted to kvllikrein and FXII becomes FXIIa
  3. series of reactions form Factor X
28
Q

common pathway of coagulation

A

FX forms FXa along with calcium and factor Va

converts prothrombin to thrombin

converts fibrinogen to fibrin

29
Q

Examples of positive feedback in the coagulation cascade

A

thrombin produces factor V, which increases actor Va

converts XIII to XIIIa

30
Q

How is fibrin formed?

A

loose fibrin- thrombin removes negatively charged fibrinopeptides, which causes the fibrin domains to aggregate

tight fibrin- factor XIIIa crosslinks the fibrin at Gln and Lys resides

31
Q

intrinsic pathway of coagulation explained

A

triggered by difference in cell surface- if it becomes negative

  1. XII to XIIa
  2. XI to XIa
  3. IX to IXa
  4. X to Xa
32
Q

What is vitamin K?

A

An essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII IX and X

33
Q

Why is calcium and phospholipid needed?

A

required for tens and prothrombinase complexes to function

34
Q

Fibrinolysis definition

A

process that prevents blood clots from growing and becoming problematic

35
Q

explain stages of fibrinolysis

A
  1. plasminogen is produced in the liver
  2. plasminogen is inactive but still has an affinity for fibrin, so binds during clot formation
  3. tissue plasminogen activator and urokinase convert plasminogen into plasmin. T-PA is produced by the damaged endothelium very slowly

Factors XIa, XIIa and Kallikrein also increase the production of plasmin

36
Q

How does plasmin work?

A

A serine protease that cleaves the fibrin, forming smaller fragments that then circulate and are cleared by other proteases or by the kidney and liver

37
Q

Key clinical problems associated with haemostasis + definitions

A

thrombosis- haemostasis in an intact blood vessel

embolism- a transported thrombus

haemorrhage- internal bleeding

thrombocytopenia- too few platelets

thrombophilia- a predisposition thrombosis

haemophilia- inherited clotting factor defects

38
Q

Two types of haemophilia + symptoms

A

Haemophilia A- low amounts of clotting factor VIII

Haemophilia B- low amounts of clotting factor IX

leads to more severe and frequent bleeds

39
Q

explain haemophilia A

A

No factor VIII, so cannot act as a cofactor for IXa, which in the presence of calcium and phospholipids wild convert X to Xa, so no thrombin formed

40
Q

explain haemophilia B

A

No factor IX, so cannot become activated in the presence of calcium and phospholipids and a factor VIII cofactor, so cannot activate X to form Xa

41
Q

Explain genetics of haemophilia

A

X linked recessive disease, so more men affected

heterozygous women are carriers

42
Q

How does factor VIII travel in the blood?

A

circulates in the inactive form bound to von Willebrand factor until an injury that damages blood vessels occurs

Blood cells- OB/Biochem (8 decks)

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