Haemostasis Flashcards by Jule Hoelscher

What is Haemostasis?

the specific, regulated cessastion of bleeding in response to a vascular injury to stop bleeding and allow vessel repair to occur

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Explain the vascular response to bleeding

Vasoconstriction to reduce blood flow and therefore bleeding

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What is primary haemostasis?
What is its funciton?

platelet adhesion
platelet aggregation that forms an
unstable white plug

–> limits blood loss + provides surface for coagulation

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What is secondary haemostasis?

What is its function?

To stabalise cloth formed in primary haemostasis

activated coagulation factors
fibrin mesh
—> stops blood loss

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What is involved in Blood coagulation

Vessel wall

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Explain the structure and function of the vasculature wall in haemostasis

Vascular wall endothelium is anti-coagulant

e.g. thrombomodulin etc.

The sub-endothelium is pro thrombotic and procuagulant basement membrane

Elastin, Collagen, TF (on vascular SM cell, fibroblasts)

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Explain the role of the vascular response to injury

st step in Haemostasis–> vasoconstriction
- most important in small vessels
- local response to injury
- to reduce blood flow

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Where are platelets derived from?

Derived from Megacaryocytes (one cell around 4000 platelets)

released as pro platelets into blood stream

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What are platelets?

What is a normal platelet count?

small
anuclear cells
lifespan about 10 days
very responsive because of many receptors that can interact with outside stiummuli
normal count: 150-350 x 10^9/L

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What is a alpha-granule in a platelet?

granule in platelet containing

growth factor
fibrinogen
VWF

–> released when activated

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What is a dense granule in a platelet?

contains

ADP
ATP
Serotonin
Ca2+ and get released when activated

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What are the role of the platelet membrane in haemostasis

In inactivated state: normal membrane

When Activated: negatve charge from phospholipids turns outside and makes surface very attractive for anti-coagulants

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How does the platelet shape changes in platelet activation?

Cytoskeleton changes:

conversion from a passive to an interactive cell

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Explain the Recruitement of platelets to the site of injury

Vessel Injury exposes collagen

VWF binds to collagen–> changes conformation that exposes binding sites on VWF for platelets

Platelets adhere to now exposed VWF via Gp1b

platelets can also adhere to collagen but only when low blood flow, it is VWF dependant

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How do platelets get activated

Different stimmuli lad to activation

Collagen
Thrombin
ADP
Thromboxane
each other via alpah2bß3

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What happens when platelets get activated ?

Relase granule

change of membrane –> negative charge
release of thromboxane
release of ADP
- more

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What are the Thrombocytopaenia levels when do certain characteristics occur?

Normal range 10-300 10⁹/l

<10 spontaneous bleeding common

<40 spontaneous bleeding

<100 no spontaneous bleeding but bleeding in trauma

Where are coagulation factors synthesised?

The liver – most plasma haemostatic proteins
Endothelial cells – VWF, TM, TFPI
Megakaryocytes – VWF, FV

What are zymogen hormones in haemostasis?

Precursors to serine proteases

What is the role of serine proteases in haemostasis?

Cleaving someting and activating it by this

–> factors have a serine protease domain at activated site

What is a Gla domain?

Where is it present

Domain that give clotting factors the ability to interact with phospholipid surfaces

VII
X
Prothrombin
IX
Protein C
Protein S

Where is Tissue factor present?

What is its role in haemostasis ?

Factor III–> binds complex with VII to set of extrinsic pathway–>

normally located at extravascular sites
- i.e not usually exposed to the blood (VSMC, fibroblasts etc…)
TF expressed higher in certain organs
- (i.e. lungs, brain, heart, testis, uterus, and placenta)
  - TF in these locations provide further haemostatic protection in these organs.

Where is Coagulation factor VII synthesised?

What is its funciton?

Circulates inactively in plasma –> Has to get activated

has Gla domain
Serine protease domain

very small amount of active factor VII citculates 1%

What is the role of vitamine K in blood coagulation?

Important in Gla domain formation:

It does post-translational modification of proteins that give rise to calcium binding site

–> calcium changes conformation, can now interact with negative phospholipid membranes

What is the mechanism of action of Warfarin?

Vit.K carboxylase antagonist --\> deminishes function of a number of clotting facotrs by impairing interaction with phospholipid membrane with Gla domain

Explain the coagulation cascase

What is Haemophilia A?

Lack of clotting factor VIII

What is Haemophilia B?

Lack of clotting factor IX

How is Haemophilia inherited?

X-chromosomal recessive

What is the role of TFPI in haemostasis?

Inhibits coagulation at site of activation --\> binds to factor Xa which then binds to complex **III+VII** --\> inactivation of all 3 proteins

Explain the role of protein C in haemostasisi

Cleave factor V and VIII --\> inhibits them

Explain the formation of protein C in haemostasis

Thrombin binds to Thrombomodulin on tissues --\> Thrombomodulin modulates thrombrin to cleave Protein C to activate it --\> shots down coagulation at edges of blood coagulation (because thrombomodulin is present at intact endothelial surface

What is the role of Antithrombin

serine protease inhibitor (not just inactivated thrombine) • AT inactivates many activated coagulation serine proteases (FXa, thrombin, FIXa, FXIa)

What is the site of action of heparine

Enhances the activity of Antithrombin to make it more effective to **inhibit Thrombin + FX**

Explain the process of fibrinolysis

Done by Plasmin --\> degrades fibrin fibres Plasmin is activated from precursor form plasminogen by tissue plasminogen activator (tpa)

Explain the clinical use and mechanism of action of tPA

tissue Plasminogen activator --\> turns plaminogen into plasmin Plasmin degrades fibrin and lyses blood cloths This can be used in thrombotic infarctions e.g. stroke, MI etc.

What is the drug group and of heparin and warfarin. When would you give it to a patient?

Thea are **anticoagulatns** Manily used for someone at risk of **venous thrombosis**

Which type of drugs would you perscribe to someone at risk of venous thrombosis?

Hepatin, warfarin, directly acting anticoagulatns --\> **Anticoagulants** (over anti-platelet agents)

Explain the mechanism of action of Asperin and its clinical use

It is an anti-platelet agent --\> irreversibly blocks COX1+2 leading to 1. reduced production of TxA2 --\> less thrombocyte aggregation (Cox1) 2. reduced prostacyclin --\> anti fever+analgesic effect Used in **arterial thrombosis**

Which type of drug (and which specific drug) would you perscribe someone at risk of arterial thrombosis?

Anti-platelet agent (Thrombozytenaggregationshemmer) --\> Asperin

What are the tests available to test coagulation?

1. Coagulation * PT time ( measures the number of seconds it takes for a clot to form in your sample of blood after reagents are added * APPT test 2. Platelet funciton test 3. d-dimer test --\> fibrin degradation product (how much clotting is happening in individual in the past)

What is the role of Protein S in Coagulation?

It is a co-factor of Protein C --\> anti-thrombotic effects