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PHARM/MHD - Exam #4 > MHD - Lec#1 - Normal Hemostasis/ Thrombosis I &II > Flashcards

MHD - Lec#1 - Normal Hemostasis/ Thrombosis I &II Flashcards

1
Q

What is the difference between a thrombus and an embolism?

A

Thrombus is a stationary clot

Embolus is a moving clot that travels from one location to another

  • Thrombus is a mass of cells & clotting proteins that occlude the blood vessels
    pressure can break down the clot and send it from legs to the lungs OR from the heart to the carotid artery and cause embolic STROKE
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2
Q

What are two important aspects of coronary clots?

A
  1. Narrowing of vessels
    - due to atherosclerosis
  2. Plaque
    - causes coagulation and activation of the coagulation cascade
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3
Q

What is the definition of abnormal hemostasis?

What is the result of abnormal hemostasis in regards to bleeding?

A
  1. Abnormal hemostasis or THROMBOSIS is a pathologic process that represents the activation of the clotting system when there are NO RUPTURED vessels. (no injury)
    - Normal hemostasis is the complex process by which ruptured vessels undergo changes which prevent blood loss.
  2. Abnormal hemostasis can also result in the loss of blood into surrounding soft tissues, into a body cavity or from the body.

Ex; cardiac tamponade results in the release of blood & leads to CHF

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4
Q

Hemostasis, both normal & abnormal depends on what 3 entities?

A
  1. Blood vessel wall (endothelium & sub endothelium)

(2) Platelets
- regulated by THROMBOPOITEIN
(erythropoitein for RBCs)

(3) Coagulation and fibrinolytic systems
* Diseases and pathologic conditions such as cancer, sepsis and congenital coagulation defects may lead to bleeding disorders.

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5
Q

______ is is a process by which blood in the vascular system remains liquid and free from clots,
and
permits the rapid formation of solid clots to
plug defects (holes) in ruptured or injured
blood vessels.

  1. When is thrombogenesis activated?
A

NORMAL HEMOSTASIS

regulated by:

  1. Platelets
  2. Endothelium
  3. Coagulation & fibrinolysis
  • Under normal conditions blood remains fluid and the cellular components of blood, (erythrocyctes, leukocytes and platelets) are not activated or physiologically altered.

Similarly the endothelial cells also remain inert.**

Only in pathologic conditions is the functional state of these components altered.

  1. Endothelial damage, activation of platelets and release of tissue factor from cells results in thrombogenesis.
    - Once a thrombus is -formed it can obstruct blood flow and produce an inflammatory response.
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6
Q

Vasoconstriction occurs immediately and briefly through what mechanisms?

What humoral factor released form endothelium does it mediate?

What is the purpose?

A
  1. REFLEX NEUROGENIC mechanisms
  2. ENDOTHELIN
  3. Serves to reduce blood loss
  • Mediators appear due to the damaged endothelin
  • constriction of the vessel occurs and the diameter is narrowed preventing the escape of blood
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7
Q
  1. ______ is a potent vasoconstricting
    agent released from the endothelial cells in distress.
    B. ______- Release of various mediators.

C. _______ - made up of contractile fibers

A
  1. endothelin
  2. Reflex Vasoconstriction
  3. Extracellular Matrix
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8
Q

What are the two major mechanisms of primary hemostasis?

A) occurs due to exposure of sub endothelial COLLAGEN as a result of injury

B) Change in the shape of platelets & chemical release

  1. What chemicals are released that recruit platelets to the site of injury?
A
  1. platelet adherence
  2. Activation of platelets
  3. Adenosine diphosphate
    - thromboxane A2
    - serotonin

serotonin acts as a peripheral vasoconstrictor

which recruit additional platelets to the site of injury and promote aggregates to form, resulting in a hemostatic plug.

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9
Q

Primary Hemostasis ( 5 major steps)

  1. Platelets adhere to the damaged vessels. Gp Ib receptor binds to what?
  2. Platelets undergo shape change, form _____ formation
  3. Light granules (alpha) release what 2 major proteins?
  4. Dense granules (beta) release ____, ____, ___, ____, ____ (5)
  5. _____. Activated platelets recruit other platelets
  6. What is the result?
  7. What determines if this is considered a pathologic process?
A

1.(GP Ib binding to vWF)

  1. discoid formation
    - (extending pseudopods)
  2. PF4, PDGF
    - and other proteins
  3. ADP, Ca+2, histamine, serotonin and epinephrine ( From DENSE beta granules)
  4. Recruitment
  5. Hemostatic plug formation. Several platelets aggregate and form a plug
  6. IF THIS PROCESS OCCURS WITHOUT EXTERNAL STIMULI like damage etc.. this is a PATHOLOGIC PROCESS!
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10
Q

Adp, Ca, histamine, serotonin & EP are released from _____

While PF4 and PDGF are released from ____

(light granule - alpha /dense granule - beta)

A
  1. DENSE granule
    - beta
  2. LIGHT granule
    - alpha
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11
Q

As primary homeostasis occurs, secondary homeostasis begins simultaneously with the release of _____ by what cells?

What ultimately forms?

A

TISSUE FACTOR by ENDOTHELIAL cells

  • released at the site of injury from the endothelial cells which combine with platelet factors to initiate the plasma coagulation cascade
  1. THROMBIN & coagulation proteins forming complexes on platelet surface
    - utilizing phospholipids of platelet membrane
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12
Q

Describe the 4 steps of SECONDARY HEMOSTASIS.

1) what is released
2) What is expressed
3) what is generated?(by activation of what?)
4) What polymerizes. Which factor is responsible?

A
  1. Tissue Factor: - Procoagulant released from various cells.
    Promotes coagulation.
  2. Phospholipid complex expression: Surface phospholipids are expressed. Promotes the coagulation process.
  3. Thrombin generation: By the activation of coagulation cascade, thrombin is generated.
  4. Fibrin polymerization: The formed fibrin is polymerized by Factor XIIIa.

(13 a!!!)

FIBRIN polymerized by 13a!

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13
Q

What is the main difference of primary and secondary hemostasis?

A

PRIMARY = platelet aggregation

Secondary= FIBRIN formation (converts fibrinogen in the platelet plug to FIBRIN)

  • secondary is due to coagulation cascade & also stabilizes the weak platelet plus formed by primary homeostasis
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14
Q

Formation of platelet-thrombin plug (permanent plug):

  1. Thrombin stimulates recruitment and activation of additional platelets and enzymatically converts ____ to ____
  2. What becomes part of the thrombus? (2)
A
  1. Thrombin enzymatically converts fibrinogen to fibrin.
  2. The consolidated platelet-fibrin clot (thrombin) forms a permanent plug which seals the hole in the vessel wall.
    - Erythrocytes and leukocytes become part of the thrombus
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15
Q

Once the clot is formed, what is it subjected to?

A

ENDOGENOUS LYSIS by fibrinolytic enzymes

  • . Clot size can also be increased due to cellular recruitment.
  • The composition of the clot depends on the vascular sites and the patients own pathophysiologic state.
  • The stationary clot (Thrombus) can also break apart and travel to another location in the vasculature (Embolus).
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16
Q

______: used to block the coagulation cascade!!!! anti-coagulant

A

THROMBOMODULIN

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17
Q

Anti-Thrombotic Effect:

a) anti-platelet effect
1. intact endothelium prevents platelets & coagulation proteins from coming into contact with what?
2. What 2 things are secreted by normal endothelial cells? Why?

A

Antiplatelet effect:

  1. Intact endothelium prevents platelets and coagulation proteins from coming into contact with subendothelial collagen.
  2. Normal endothelial cells secrete
    a) - prostacyclin
    b) - nitric oxide
    that prevent platelet aggregation.

NO = potent vasodilator
- can help with anginal pain

Prostacyclin - give aspirin to block the coagulation mechanism & pro-thrombotic mechanism

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18
Q

anti-thrombotic effect

b) AntiCoagulant Effect:

A) Heparin-like molecules, combine with a naturally occurring anticoagulant protein, ______, to inhibit thrombin & other coagulation factors.

B) _____ combines with thrombin creating a complex that activates what?

C) What cofactor does the endothelium secrete which is necessary for activation of the answer in B.

A

Anti - COAGULANT (not platelet)

  • The endothelial cell membrane contains receptors which play an indirect role in anticoagulation.

A) Heparin-like molecules, combine with a naturally occurring anticoagulant protein, ANTITHROMBIN, to inhibit thrombin & other coagulation factors.

B) Thrombomodulin, combines with thrombin creating a complex that activates protein C.

C) The endothelium also secretes protein S which is a cofactor for protein C activation.

Summary:
anti-coagulant effect 
a) thrombomodilin
b) antithrombin
c) Protein C
d) Protein S
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19
Q

Anti-Thrombotic Effect

C) FIBRINOLYTIC EFFECT:

  1. Endothelial cells also secrete ______ which promote fibrinolysis.
  2. Plasminogen is converted to _____ and dissolves the clot.
  3. Activated _____mediates proteolytic degradation of Factor Va and VIIIa.
A
  1. plasminogen activators (t-PA)
  2. Plasmin
  3. Protein C
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20
Q
  1. What 2 major proteins are responsible for the inhibition of platelet aggregation?
  2. Heparin like molecule binds Anti-thrombin which inactivates thrombin and inactivates what 2 factors?
  3. Thrombin binds thrombomodulin, resulting in activation of protein C in the presence of Protein S which results in what?
  4. tPA converts what to what?
A
  1. NO & prostacyclin
  2. Factors Xa and IXa (10 and 9a)
    - heparin enhances the activity of antithrombin
  3. Proteolysis of Factors Va and VIIIa
  4. Plasminogen to plasmin!
    - degrades fibrin by promoting fibrinolysis!
    - clot is dissolved

a) cleavage of fibrin mesh
b) destruction of coagulation factors

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21
Q

Pro-thrombic effect:

Normal endothelial cells inhibit platelet adherence and prevent blood clotting.

  1. _____ causes a loss of these anticoagulant mechanisms.
  2. Endothelial cells secrete _____ a protein, which forms a molecular bridge between platelets and sub endothelial collagen.
  3. Simultaneously, endothelial cells:
    synthesize and secrete ______, which activates the extrinsic sequence of the coagulation cascade.
  4. What is the role of cytokines released by injured endothelial cells?
A
  1. Injury
  2. von Willebrand Factor

Platelet adhesion to endothelial cells occurs!

  1. tissue factor
  2. Cytokines released by injured endothelial cells can stimulate cells to synthesize more tissue factor. (many inflammatory cytokines)
22
Q

Where is von willebran factor from?

What is the role of tissue factor? (2)

A
  1. Weibel Palade bodies of endothelial cells & alpha-granules of platelets

2.
a) promotes the generation of THROMBIN and formation of a clot.

b) Once the clot is formed it traps other cells such as erythrocyctes and leukocytes.

23
Q

What are platelets?

What mediates the attachment of platelets to sub endothelial proteins via VWF?

What do light granules of intra-cytoplasmic platelet granules contain? (alpha)

  • Which 2 factors specifically?
  • What serves as a heparin binding chemokine?

Dark granules? (beta)

A
  1. Platelets are discoid, anuclear cells which play a major role in hemostasis.
  2. Glycoprotein receptors
  3. Platelet Factor 4 (heparin binding chemokine - causes heparin induced thrombocytopenia)
    - PDGF
    - Fibrinogen
    - fibronectin
    - factors V and VIII
    - TGFB
    • ADP
    • ATP
    • ionized calcium
    • histamine
    • serotonin
    • EPI
24
Q

What are the 2 most important platelet receptors?

What are their functions?

A

Glycoprotein IIb/IIIa:

  • responsible for forming the platelet bridge
  • AGGREGATION promoted by binding of fibrinogen & GpIIb/IIIa

GlycoproteinIb:
- Platelet ADHESION initiates clot formation and depends on
vWF and platelet glycoprotein Gp1b.

Other receptors:

  1. Thrombin
  2. Serotonin
  3. ADP
25
Q

Bernad - Soulier syndrome is due to a deficiency of _____

Glanzmann thrombasthenia is due to deficiency of ____

A

Glycoprotein IB deficit!
(1b for bernad)

GpIIb/IIIa

(Bernard Soulier is 2 words, but 1 protein deficiency while Glanzmann is 1 word and 2 receptor deficiency)

26
Q

With vessel injury, circulating platelets are exposed to _____ , _____, _____ (3) which cause what 3 reactions?

A
  1. Exposed to sub endothelial proteins
    - collagen
    - proteoglycans
    - fibronectin
  2. Adhesion
  3. Activation & Secretion
  4. Aggregation
27
Q

What occurs in ADHESION (the 1st reaction that occurs due to platelet injury causing primary hemostasis changes?

  1. Platelets attach to _____ through a molecular bridge
  2. GPIb attaches to ____ which in turn attaches to _____
  3. What is the main purpose of adhesion?
A
  1. Platelets attach to the subendothelial collagen through a molecular bridge.
  2. The platelets plasma membrane, glycoprotein receptor (GP Ib) attaches to the von Willebrand factor which in turn attaches to collagen.
  3. Adhesion is a critical reaction because it prevents the blood flow from dislodging the adherent platelets and unplugging the defect in the vessel wall.
28
Q

4 major steps of Platelet plug formation

  1. Injury
  2. Exposure
  3. Adhesion
    4a. Activation
    4b. Aggregation
A 
1. Endothelial damage
 transient
vasoconstriction via
neural stimulation reflex
and endothelin (released
from damaged cell)
2. EXPOSURE
vWF binds to exposed
collagen
vWF is from Weibel-Palade
bodies of endothelial
cells and -granules of
platelets
3. Adhesion:
Platelets bind vWF via GpIb receptor at the site of injury only (specific)  platelets undergo conformational
change
- Platelets release ADP and
Ca2+ (necessary for
coagulation cascade), TXA2
- ADP helps platelets adhere
to endothelium
4a. ACTIVATION
ADP binding to receptor
induces GpIIb/IIIa
expression at platelet
surface

4b. AGGREGATION
Fibrinogen binds GpIIb/IIIa receptors and links platelets
- Temporary plug stops bleeding; unstable, easily dislodged

  • secondary hemostasis is the coagulation cascade
29
Q

What is the result of a vWF deficiency?

A

Deficiency in VWF = von willebrand disease

– platelet will not adhere and cause bleeding
- increase bleeding time, increase PTT
(normal PT)

TX: desmopressin which increases vWF release from weibel-palade bodies of endothelial cells

30
Q

ACTIVATION of Platelets:

  1. Activation of platelets is initiated by molecules binding with platelet membrane ______ receptors
  2. Upon activation platelets release other granular content including such substances as coagulation factors, __2__, __3__ and ___4___
  3. What activities the phospholipid complex?
  4. This complex serves as a site on which coagulation factors combine with ______ to activate the intrinsic pathway.
A
  1. GP IIb/IIIa receptors.
  2. ADP,
  3. calcium
  4. and thromboxane A2.
  5. The phospholipid complex is activated when negatively charged phospholipids become exposed on the platelet surface.
  6. ionized calcium
31
Q

AGGREGATION of Platelets:

  1. Release of ADP and _____ from activated platelet granules initiates a reaction which serves to recruit, activate and aggregate platelets.
  2. _____ and _____ released by platelet granules, vasoconstrict the vessel, decreasing the size of injury, reducing blood flow and the likelihood of the plug detaching from the vessel wall.
  3. Simultaneously, _____ is formed by the activation of the intrinsic pathway (ADP, calcium, coagulation factors, phospholipid complex).
  4. _____ also converts fibrinogen to fibrin.

Fibrin surrounds and structurally holds platelets in a secondary (irreversible) hemostatic plug.

A
  1. THROMBOXANE A2
  2. Serotonin and thromboxane A2
  3. thrombin
    - Thrombin, ADP and thromboxane A2 accelerate platelet aggregation.
  4. Thrombin
32
Q

COAGULATION SYSTEM:

  1. Fibrinogen is a soluble protein which is converted into a gelatinous mesh upon the action by ______ which is known as FIBRIN.
  2. The fibrin clot is stabilized by what two things? (state the factor for the first one)
A
  1. thrombin (IIa)
  2. a transamidase enzyme (XIIIa) and
    TAFIa

Thrombin activatatable fibrinolytic inhibitor (TAFI)

33
Q

What test is used for the intrinsic pathway?

What activates this cascade?

What drug is related to intrinsic pathway?

Hemophilia A & B are deficiencies of what factors in the intrinsic pathway?

How can this be detected clinically?

A
  1. APTT
    - endogenous mechanisms like sepsis, stents/heart valves
  2. Heparin
  3. Hemophilia A = definiciy of factor 8
    Hemophilia B = deficiency of factor 9
  4. Detect by increased APTT (PTT)
34
Q

What measures the EXTRINSIC pathway of coagulation?
What activates this cascade?

What drug inhibits this pathway?

Which factor?

A
  1. PT
    - external trauma, incision, car accident ( tissue factor is released which converts 7 to 7a)
  2. Coumadin/warfarin
  3. Factor 7!
35
Q

What is the only TRANSAMINASE in the coagulation cascade? (the rest are serene proteases)

A

FACTORXIIIa

13a
- known as fibrin stabilizing factor

36
Q

Initiation of either the extrinsic or intrinsic pathways results in the formation of _____ which transforms fibrinogen to fibrin.

What factors are in the fibrinogen group?

What factors are in the prothrombin group?

Which group contains the factors that are synthesized in the liver and vitamin K dependent and also contain gamma-carboxy-glutamic acid?

A
  1. thrombin
    - Factor X plays a central role in the generation of thrombin by the intrinsic and extrinsic pathways.
  2. Factors I, V, VIII, XIII
    (1, 5,8,13)
  3. Factors II, VII, IX, X
    (2,7,9,10)
    - PROTHROMBIN group
    = made in liver, vitamin K dep, carboxy glutamic acid
  • EX: patient with Liver disease & bleeding
  • the likely reason of this condition is defect in lack of 2,7,9,10 synthesis & functionality!
  • measured by PROTHROMBIN TIME (INR/PT) – diagnose liver disease by a decrease in these factors
37
Q

Vitamin K antagonists inhibit the carboxylation process of what factors?

A

PROTHROMBIN factors

2,7,9,10

38
Q

What factors belong in the CONTACT group? (test)

How would defects in this group be recognized? (what test)

A

Factors XI, XII, Fletcher Factor (prekallikrein), Fitzgerald Factor (HMW Kininogen)

  1. Recognize by APTT
39
Q

Inhibitors of the coagulation system, what are the 2 major inhibitors?

A
  1. Antithrombin III (AT)
    - same anti-thrombin which is a heparin cofactor and heparins effects are augmented by this factor!
  2. Tissue Factor Pathway inhibitor (TFPI)
  • heparin cofactor II (II)
  • inhibitors to clotting factors
  • Lupus anticoagulant & anti - phospolipid antibodies
  • Antibodies to coagulation factors
40
Q

_____ is a plasma inhibitor which also mediates the anticoagulant actions of heparin.

Heparin cofactor II is a weak inhibitor of ____.

Tissue factor pathway inhibitor is a potent inhibitor of _____.

A
  1. Antithrombin
  2. thrombin
  3. tissue factor
41
Q

What lyses the clot formed by fibrin?

What activates this fibrinolytic system?

A

PLASMIN

(fibrinolysin)

  1. Plasminogen is converted by plasminogen activators into PLASMIN
42
Q

What are the 4 important inhibitors of the fibrinolytic system?

A
  1. Plasminogen activator inhibitor (PAI)
  2. alpha2-antiplasmin
  3. alpha2-macroglobulin
  4. Thrombin activatable fibrinolytic inhibitor (TAFI)
43
Q

tPA and urokinase can convert ____ to ___

Resulting in what?

What can inhibit tPA?

A

Plasminogen to Plasmin

  • clot digestion
  • fibrin degradation products form!
    3. PAI can inhibit tPA
44
Q

Fibrin Degradation products can be used to determine what?

A

DIC!

45
Q

_____ can be defined as a pathologic transition of the state of blood from fluidity to non-fluidity.

A

Thrombosis

  • The stationary clot (thrombus) may progress and eventually break into smaller pieces which when released into blood circulation are called emboli (embolus).

Many factors are responsible for the process of thrombogenesis.

  • The thrombogenic mechanisms differ in the arterial and venous systems.
46
Q

What are some factors that influence the differences in thrombogenic mechanisms of the arterial & venous systems?

A
  • Blood flow
  • endothelial cell composition
  • size of blood vessel
  • degree of oxygenation
47
Q

What are the 3 major factors contributing to Virchow’s triad?

A
  1. endothelial injury (result is release of tissue factor)
  2. Hypercoaguable state - Alterations in blood composition
  3. Stasis (abnormal blood flow)
48
Q

What is the hypercoaguable state?

What plays a role?

A

Imbalance of the blood coagulation mechanisms leading to thrombotic transitions.

  • Age, smoking, oral contraception and diet also play important roles in contributing to a hypercoagulable state.

Thrombotic stroke, myocardial infarction and peripheral arterial thrombosis result from this syndrome.

49
Q

What are the 2 PRIMARY hypercoaguable (genetic) states?

A
  1. Molecular thrombophilias

2. Inhibitor deficiency

50
Q

What are secondary (acquired) hypercoaguable states?

  1. High risk (3)
  2. Low risk (3)
A
  1. High Risk:
    Sepsis
    Cancer
    Trauma
  2. Low Risk:
    Pregnancy
    Hyperlipidemia
    Drugs
51
Q

What are some molecular basis of Thrombophilia?

What are the clinical manifestations of thrombophilia?

A
  1. Factor V Leiden,
  2. Prothrombin 20210
  3. Methylenetetrahydrofolate reductase (MTHFR mutation
  4. DVT
  5. Microbascular angiopathic conditions

PHARM/MHD - Exam #4 (20 decks)

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