27. Hemostasis & Clotting Flashcards by Priyanka Barad

what are platelets derived from

megakaryocytes

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what is a normal platelet count

150,000 - 400,000 / uL

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what is considered a low platelet count

<50,000

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what is a potentially lethal platelet count

<10,000

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what makes the cytoskeleton of platelets

actin, myosin & thrombosthenin

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what organelles do platelets have & what is its purpose

Mitochondria- attach and contract

ER, golgi remnant - store Ca

dense-core granules & alpha-granules

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what substances are in platelets

Cox-1 (makes thromboxane A2)

5-HT -vasoconstict

fibrin stabilizing factor (clot stability)

platelet derived growth factor (repair)

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what controls platelet regulation

thrombopoietin

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what is TPO make by

liver & kidneys

*regulation will be affected w/ kindey/liver failure*

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how does TPO fxn

increase differentiation & maturation rate of hematopoietic stem cells

–> more megakaryocytes & platelets

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what receptor does TPO bind to on platelets & megakaryocytes

c-MPL (CD-110)

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when you have high platelet count, TPO will —

be bound to c-MPL –> internalized and degraded in platelets/megakaryocytes –> little free TPO available

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if you have low platelet count, then what happens to TPO

little TPO bound to c-MPL –> NOT degraded so more free TPO available

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what are the 4 basic steps of hemostasis

- Vascular spasm
- Formation of platelet plug
- Formation of blood clot
- Repair of damage

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what is the purpose of vasospasm

disrupt blood flow by contracting upstream to prevent blood loss

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what factors contribute to vasospasm

Myogenic: response to damage to smooth muscle
Serotonin and TXA2
Release of molecules from endothelial cells
neural reflex initiated by mechanical injury and/or pain

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which proteins do platelets adhere to beneath the endothelial lining during vascular injury

collagen and laminin

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what prevents platelets from adhering to endothelium in normal situations

negative charge of glycoproteins

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What is the role of von Willebrand factor?

produced by endothelial cells and by platelets

—serves as a ligand for platelet receptors

–> activate platelets –> bind fibrinogen –> help form platelet plug

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what do dense granules release once platelet receptors are activated

release ATP, ADP, 5-HT & Ca

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What is the platelet receptor for collagen?

Gp Ia/IIa

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What platelet receptor does lamnin bind

Gp Ic/IIa

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what do alpha granules release when platelet receptors are activated

release growth factors, vWF, factor V & fibrinogen

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what does ADP bind to activate platelet aggregation

& what medication inhibits this

P2Y12 receptor

inhibited by plavix (clodpidogrel) - antiplatelet agent

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what does aspirin bind to inhibit clotting

cyclooxygenase receptor -by reducing release of thromboxane A2 --\> reduce clotting

how does blood clot form

thrombin generate fibrin --\> stimulate polymerization and contraction of clot

How are vessel walls repaired?

platelet-derived growth factor stimulates fibroblasts to grow into the area differentiation for remodeling

What is the role of protein C in clot breakdown?

inactivates the t-PA inhibitor no tPA is active --\> so it converts plasminogen to plasmin --\> which remove & lyse fibrin

what does fibrin inhibit

thrombin limit clotting

What is the function of prostacyclin?

vasodilation and a potent inhibitor of platelet aggregation limit clotting

When does antithrombin III act as an anticoagulant?

when it is bound with thrombin

what does heprin do

increase anti-thrombin efficacy | (from mast cells)

Which factors are utilized by the extrinsic clotting pathway? & when is it activated

Factor III (tissue factor) --\> **Factor VII**/TF complex --\> Xa activated by external trauma & quick

Which factors are utilized by the intrinsic pathway? & when is it activated

Factors **XIIa \> XIa \> IXa + VIII** \> Xa -actived by truama inside (vasculature, platelets, exposed endothelium, chemicals or collagen) = slow

Which factors are utilized by the common pathway?

Factor Xa + V \> Thrombin (IIa) \> Fibrin (Ia) include factors **I, II, V, & X**

What is the primary difference between primary and secondary hemostasis?

primary makes a weak platelet plug secondly makes it strong by generating a fibrin mesh on it

What does thrombin activate?

Factors V, VIII, XIII protein C prothrombin fibrinogen

Which clotting cascade is activated first?

extrinsic pathway

How does activation of the extrinsic pathway cause activation of the intrinsic pathway?

activation of the common pathway, and specifically thrombin, has a positive feedback on factors upstream

What is the function of antithrombin?

inhibits further cleavage of prothrombin and inhibits the production of factor Xa from X

What are the two types of short acting oral anticoagulants? What is their MOA?

Hydroxycoumarins (warfarin/coumadin) and indanediones --\> inhibit the action of vitamin K

In which form is vitamin K active?

quinol form ( converted in liver via quinone reductase ) --\> form blood clots

Which enzyme does warfarin decrease the activity of?

Vit K-dependent epoxide reductase --\> which is responsible for converting vitamin K to the quinone form

What is vitamin K a cofactor in synthesizing?

Active Factors II, VII, IX, and X, protein S and C (these are anticoagulant proteins)

What is the product of the carboxyglutamination reaction?

1. glutamate (gamma-carboxyglutamate) --\> more negatively charged --\> recruits activated clotting factors 2. -Vit K oxidized back to VIt K 2,3 epoxide 3. activate 2,7,9,10, protein C & S

What can be used for a warfarin overdose?

vitamin K

What is added to the gamma-glutamate residue on Factors II, VII, IX, and X?

carboxyl group

Which enantiomer of warfarin is more potent?

S-enantiomer is 2-5X more potent than R-enantiomer in produding anticoagulant response

Which CYP enzyme metabolizes S-warfarin?

CYP2C9

If a patient is on a drug or eating a lot of food that is metabolized by CYP2C9, what would be the effects?

Increase the blood concentration of active S-warfarin- -\> increasing the potency (metabolism of drug is inhibited)

What is the half life of Factor II?

60 hours

What is the half life of Factor VII?

4-6 hours

What is the half life of Factor IX?

24 hours

What is the half life of Factor X?

40-60 hours

Which factors do protein C and S inactivate?

proteolytically inactivate **_Va and VIIIa_** --\> degrades clot

What is the risk of a protein C deficiency?

significantly increased risk of venous thrombosis

What is hemophilia A?

**factor VIII** deficiency Genetic disorder, but 1/3 are caused by a spontaneous mutation

What is hemophilia B?

factor IX deficiency also called Christmas disease

What is hemophilia C?

Factor XI deficiency

What is INR?

International Normalized Ratio measures blood clotting time and compares it to normal values.

What is prothrombin time (PT) measuring?

Factors I, II, V, VII, and X ( extrinsic coagulation pathway )

What is partial thormboplastin time (PTT) measuring?

Factors XII, XI, IX, VIII, X, V, II, and I && prekallikrein (PK) and HK Measures integrity of intrinsic and common clotting pathways

how would liver diease affect PT & PTT

PT- prolonged PTT- normal

what is the fxn of tPA

conversion of plasminogen to plasmin --\> cleave thromib & fibrin clots --\> actively lyse clots

what is used for the activation of antithrombin III

anticoagulant (heparin) -rapid, prevent clot

what impairs the synthesis of vit K dependent clotting factor

anticoagulant - warfarin -slow- prevent clot

what irreversibly inhibits cyclooxygenase & what is the consequence

aspirin -inhibit platelet aggegration & prevents glot formation (slow)

what can cause PT to be prolonged & PTT to stay normal

**liver disease** **decreased vit K,** decreased/defective factor **VII,** anticoagulation drug (**warfarin**) therapy) chronic low-grade dissminated intravascular coagulation,