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Cardiology M2 > 11 07 2014 Hemostasis > Flashcards

11 07 2014 Hemostasis Flashcards

1
Q

What is the primary initiating event of hemostasis?

A

hemostasis: bleeding and clotting

Damage to a blood vessel/ endothelium injury
- blood exposed to tissue factor, von willebrand factor, collagen

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2
Q

What is a platelet and where does it come from

A

produced in bone marrow– bleb off of megakaryocytic cytoplasm. They contain granules full of important chemicals.

Life span is 7-10 days

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3
Q

Primary Hemostasis

A

Formation of platelet plug

  1. Activation:
    When blood vessel is damaged, sub endothelial cell matrix is exposed ( collagen* and vWF and Tissue Factor)

vWF is released from damaged endothelium and binds to exposed collagen

  1. Adhesion
    Platelets attach to vWF via GPIb receptor
  2. Aggregation

Binding of platelets to vWF activates platelet cell surface receptors : GPIIb/IIIa
- binds fibrinogen
= 3D platelet-fibrinogen mesh = Platelet plug

Changes shape of platelet (pseudopods and platelet granulation)

  1. Secretion:
    Degranulation – release of granules (alpha granules and dense bodies- increase aggregation and platelet activation) activates more platelets = bind to fibrinogen and make a thicker platelet plug
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4
Q

What are the receptors on platelets crucial for hemostasis?

A

GPIIb/ GPIIIa
GPIb

Absence of above = Glanzmann’s thrombasthenia, bernard Soulier syndrome

Facter V and III receptors ( and maybe VIIa receptor)

receptors for neutrophils, monocytes

  • components of dead neutrophils can activate platelets and other clotting events
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5
Q

Von Willebrand Factor (vWF)

  1. describe protein
  2. who processes it and why?
  3. Where is it usually found?
  4. What are the two important functions of vWF?
A

protein - multimer

Rapidly processed by ADAMTS13 metalloprotease
- if not processed = bind and activate platelets in an unregulated manner

Found in alpha granules of platelets OR in vascular endothelium cells

  1. facilitates platelet adhesion to the vessel wall by linking platelet membrane receptors to the subendothelial matrix
    “ the glue”
  2. plasma carrier for factor VIII
    - extends half-life of Factor VIII from 8-15min to 13 hours
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6
Q

Details about the process of Secretion in primary hemostasis. Explain why aspirin/ NSAIDs interfere with platelet function

A

Granule secretion is a phospholipid dependent event

Exposure of the platelet to collagen initiates a series of events in which arachidonic acid (lipid bilayer of the platelet) is converted to thromboxane A-2 by cyclo-oxygenase 1 (Cox-1)

Presence of thromboxane A-2 = secretion
- it is also a potent vasoconstrictor (enhancing blood stasis

Aspirin blocks COX-1

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7
Q

What exactly do dense bodies do and what is the name of the syndrome when they are not present?

A

Dense bodies are stored in the granules of platelets. They increase platelet activation

Syndrome: Hermansky-Pudlak syndrome

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8
Q

Severe Thrombocytopenia

  1. causes
  2. signs/symptoms
A

decreased platelet numbers.

  1. not being made
  2. being destroyed
  3. sequestered – Check spleen

Bleeding in mouth and gums
Bruising
nosebleeds
petechia– pinpoint red dots

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9
Q

Von Willebrand disease

A

Autosomal Dominant
deficiency of VWF = can’t stop a bleed after an injury quick enough.

Recall that vWF carries factor 8!! So deficiency in VWF = have an effect on factor 8 (may be less because of short half life when vwf is not around)

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10
Q

What causes a prolonged bleeding time

A
  1. vascular fragility
  2. Collagen abnormality (Marfan syndrome)
  3. Low platelet count
  4. low or abnormal vWF
  5. Abnl platelet function
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11
Q

PT test

A

Prothrombin time

Evaluates the extrinsic coagulation system down to the formation of the fibrin clot
* VII, X, V, II, I (separate test)

Normal reference is 11 to 15 seconds

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12
Q

PTT test

A

Partial Thromboplastin time

Evaluates the intrinsic coagulation system down to formation of a fibrin clot
* VII, XI, IX, VII, X, V, II, I

Normal reference is 25- 40 secs

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13
Q

What would you suspect if PT is prolonged?

A

Fact VII deficiency

- life threatening bleeds

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14
Q

What would you think of if a patient has a prolonged PTT?

A

deficiency: 8, 9, 11, 12

Factor 12 deficiency has no bleeding problems

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15
Q

PT and PTT are both prolonged

A

Factor II deficiency, V, 10

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16
Q

Platelet Function Analyzer –PFA- 100 test

A

measures time for platelets under shear stress to clot off aperture
- glass tube coated with collagen and epinephrin or ADP (platelet activators)

specific for vWD and platelet dysfunction but NOT sensitive to common late let defects

  • this is not a screening test, it is a diagnostic test
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17
Q

PFA- 100 test

A

measures time for platelets under shear stress to clot off aperture

specific for vWD, not sensitive to common late let defects

  • this is not a screening test, it is a diagnostic test
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18
Q

Platelet flow cytometry

A

Platelets are labelled with antibodies directed against surface membrane glycoproteins

CD41— GpIIB
CD61 – GPIIIa
CD42b — GPIb : inhibits ristocetin – depndent binding of vWF

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19
Q

Platelet flow cytometry

A

Platelets are labelled with antibodies directed against surface membrane glycoproteins

CD41— GpIIB
CD61 – GPIIIa
CD42b — GPIb : inhibits ristocetin – depndent binding of vWF

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20
Q

Ristocetin

A

antibiotic that causes clotting

— the platelets clot in presence of von Willebrand factor when exposed to this antibiotic

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21
Q

Aspirin

A

irreversibly acetylates and inhibits platelet COX-1

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22
Q

Clopidogrel

A

blocks ADP activation of GPIIb/ GPIIIa receptor complex

- block binding to fibrinogen = block the 3D platelet plug

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23
Q

ReoPro or Abciximab

A

Anti- integrin monoclonal antibody that binds GP IIb/ IIIa

- block binding to fibrinogen = block the 3D platelet plug

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24
Q

ReoPro

A

Anti- integrin monoclonal antibody that binds GP IIb/ IIIa

- block binding to fibrinogen = block the 3D platelet plug

25
Q

Is the platelet plug strong? Will it stay put?

A

no, one can brush it away very easily and therefore keep bleeding. We need to do something else to strengthen the platelet plug

26
Q

Platelet Count

A

normal : 150,000 to 400,000 cells/mm^3

27
Q

Bleeding time test

A

Evaluates platelet function up to the formation of temporary platelet thrombus

Normal interval is 2-7min

28
Q

Steps of the intrinsic pathway of secondary hemostasis

A

Factor 7 is activated
Activates 11
Activates 9 (with the help of factor 8)
Activates 10 –> common pathway

29
Q

Steps of the intrinsic pathway of secondary hemostasis

A

Factor 7 is activated
Activates 11
Activates 9 (with the help of factor 8)
Activates 10

30
Q

Steps of the extrinsic pathway of secondary hemostasis

A

Factor 7 is activated via tissue factors

Activates factor 10 —> common pathway

31
Q

What is the new Cell based model of hemostasis/ “physiological pathway”

A
  1. Tissue injury = TF is exposed (non enzymatic lipoprotein). TF binds Factor 7 = active complex
  2. TF- 7a complex catalyzes the activation of X –> Xa and 9 –> 9a
  3. 10a in the presence of factor 5a activates prothrombin (II) to thrombin
  4. Thrombin activates 5, 8, 9, 10 —> further platelet aggregation
  5. 9a in the presence of 8a activates 10 –> 10a (on platelet surface)
  6. 10a in the presence of 5a catalyzes prothrombin to thrombin
  7. 7a bound to platelet surface acti gates 10
  8. 11 activated by thrombin. Then 11a activates factor 9
  9. Thrombin IIa catalyzes the conversion of fibrinogen to fibrin
32
Q

What is the new Cell based model of hemostasis/ “physiological pathway”

A
  1. Tissue injury = TF is exposed (non enzymatic lipoprotein). TF binds Factor 7 = active complex
  2. TF- 7a complex catalyzes the activation of X –> Xa and 9 –> 9a
  3. 10a in the presence of factor 5a activates prothrombin (II) to thrombin
  4. Thrombin activates 5, 8, 9, 10 —> further platelet aggregation
  5. 9a in the presence of 8a activates 10 –> 10a (on platelet surface)
  6. 10a in the presence of 5a catalyzes prothrombin to thrombin
  7. 7a bound to platelet surface acti gates 10
  8. 11 activated by thrombin. Then 11a activates factor 9
33
Q

Factors V and VIII

A

co-factors with no enzymatic activity of their own.

Va —> activates 10 —> Prothrombin
VIIIa –> activates 9 –> activates 10

People missing factor V or VIII make clots, but not as fast.

  • similar clinical appearance between factor 8 and 9 deficiencies
34
Q

Who are the factors that require vitamin K?

A

Factors 2, 7, 9, and 10
- they are gamma - carboxylated proteins that require vitamin K to become carboxylated

  • carboxylation takes place in LIVER

Can’t give liver patient with low thrombotic factors vit. K
- bad liver failure all thrombotic factors EXCEPT 8 will be low. – made by endothelial cells too along with vWF

and Protein C and S - anti-coagulation

35
Q

Hemorrhagic Disease of the newborn

A

Give infants vitamin K shots to prevent hemorrhaging

36
Q

Factor 13

A

fibrin stabilizing factor; activated by thrombin to covalently cross-link the fibrin polymers

  • provides clot strength
  • Without factor 13, clots dissolve more rapidly

Comes in after fibrin is made therefore it is not picked up by PT or PTT test.

  • D-Dimer!!!
37
Q

Factor 13

A

fibrin stabilizing factor; activated by thrombin to covalently cross-link the fibrin polymers

  • provides clot strength
  • Without factor 13, clots dissolve more rapidly

Comes in after fibrin is made therefore it is not picked up by PT or PTT test.

38
Q

Thrombin time

A

clinical test that measure the amount of time it takes to convert fibrinogen to fibrin

low levels of fibrinogen or dysfibrinogenemia will show prolonged thrombin times.
- usually have normal PT or PTT

39
Q

Heparan Sulfate and Thromodulin

A

normal endothelial cells express heparan sulfate and Thrombomodulin on their surface.

Both play an active role in turning off thrombin

When endothelium is damaged, that localized area now lost protective mechanism that prevented a blood clot

40
Q

How does heparan sulfate work?

A

binds to Antithrombin (AT) protein synthesize by liver AND endothelial cells.

Makes AT-Heparan complex – directly turns off thrombin and inactivates 10a

41
Q

How does heparan sulfate work?

A

binds to Antithrombin (AT) protein synthesize by liver AND endothelial cells. It helps turn off thrombin

42
Q

AT deficiency

A

rare, autosomal dominant thrombotic disorder

Do not respond well to heparin (medication that mimics Heparan)

Homozygous AT deficiency is lethal in utero

43
Q

How does thrombomodulin work

A

Thrombomodulin- thrombin complex!

Activates Protein C.

44
Q

Protein C and S function?

A

Protein C turns of 5a and 8a by cleavage at specific sites

Protein S co-enzyme of Protein C and is necessary for full activation of Protein C.

45
Q

Protein C and S deficiencies?

  1. type of inheritance
A

Autosomal dominant thrombotic disorders

46
Q

Factor V Leiden (FVL)

A

point mutation on gene for factor V = conformational change in the binding site for PC.

Va is resistant to cleavage
-Activated protein C resistance

47
Q

Factor V Leiden (FVL)

A

point mutation on gene for factor V = conformational change in the binding site for PC.

Va is resistant to clotting

48
Q

Fibrinolysis (in general)

A

process of breaking down the clot

  • measure fibrin split products (FSP)
    High levels of FSP =increased fibrinolysis
    If fibrinogen or fibrin and FSP are low = liver failure
49
Q

Fibrinolysis (in general)

A

process of breaking down the clot

50
Q

Tissue plasminogen activator (tPA) and urokinase (to a lesser degree) roles?

A

both are serene protease which convert plasminogen to plasmin. Plasmin then breaks down the clots (recall that plasmin is incorporated into the clot via attachment to fibrinogen and fibrin)

= fibrin split products (FSP) are debris from this process

used to open occluded blood vessels

  • Pulmonary Embolism
  • Stroke
  • heart attack
51
Q

Tissue plasminogen activator (tPA) and urokinase (to a lesser degree) roles?

A

both are serene protease which convert plasminogen to plasmin

52
Q

D-dimer

A

specific FSP – covalent cross linking is resistant to fibrinolysis

D-dimer are specific to fibrinolysis of an actual clot.

53
Q

Plasminogen activator inhibitor-1 (PAI-1)

A

down regulation of tPA.

Deficiency = bleeding disorder since it leaves tPA unopposed.

54
Q

alpha2 antiplasmin

A

circulating plasma protein that scavenges up free circulation plasmin. Deficiency = bleeding disorder since plasmin wandering around the body would actively break down every clot in the body.

  • alpha 2 k.o in mice does not bleed but is resistant to injury induced pulmonary embolism
55
Q

Anti-thrombin

A

made in liver and endothelium
-most important inhibitor of thrombin and 10s

Directly binds and blocks thrombin, 9a, 10a, and 11a

Action is enhanced by heparan sulfate

56
Q

Function of heparin?

A

keeps clot from growing but it doesn’t break it down.

blood thinner

57
Q

Dysfibrinogenemia

A

A variety of disorders resulting from mutations which may render a clot:

  1. resistant to fibrinolysis
  2. most sensitive to lysis
  3. resistant to cross linking

some result in both bleeding and clotting disorder

58
Q

What are some inherited thrombophilia (endothelial cell)

A
  1. endothelial protein C recpetor mutations
  2. Kruppel-like factor KLF2 polymorephisms
  3. Endothelial apoptosis
  4. Variable expression of ADAMTS-13

Cardiology M2 (25 decks)

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