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Pharmacology N929 > Coagulation and Dissolution of a Blood Clot > Flashcards

Coagulation and Dissolution of a Blood Clot Flashcards

1
Q

mechanism of blood coagulation: hemostasis sequence of events (4)

A

vasoconstriction
platelet plug
clot strengthening
clot dissolution

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2
Q

extrinsic pathway of hemostasis

aka tissue factor pathway

A

plasma mediated, initiation of hemostasis aka primary hemostasis.

  • following damage to blood vessel, factor VII comes into contact with tissue factor and forms activated TF-VIIa complex.
  • the TF-VIIa circulating the plasma activates factor X to promote the conversion of X to Xa
    key: tissue factor
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3
Q

intrinsic pathway of hemostasis

aka contact activating system

A

amplifies and propagates hemostasis aka secondary hemostasis

  • formation of primary complex on collagen and thrombin generation by way of factor XII and ultimately merges to common pathway and activates factor X
    key: thrombin
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4
Q

what does the common pathway result in

A

insoluble fibrin clot

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5
Q

normal hemostasis definition

A

a balance between generation of hemostatic clots and uncontrolled thrombus formation

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6
Q

preoperative coagulation testing

A

should be based on patients history and planned surgery**
ex) on warfarin, check INR. know b/c asked about hx
balance between risk of surgical bleeding and risk of developing postoperative thromboembolism

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7
Q

agents for anticoagulation (4)

A

antiplatelets (asa, plavix)
anticoagulants (heparin, warfarin)
thrombolytics (TPA)
procoagulants (FFP, topical agents)

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8
Q

hemostasis

A

precisely regulated by interactions between blood vessel walls, circulating platelets, and clotting proteins in plasma

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9
Q

fibrinolysis

A

orderly breakdown of stable blood clot

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10
Q

what happens when a vessel is ruptured?

A

normally, anticoagulants predominate but when a vessel is ruptured, procoagulants are activated

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11
Q

clot formation at vascular injury site

A

initiation: binding of platelets to collagen. Tissue factor (TF) dependent initiation of coagulation
propagation: recruitment of platelets to growing thrombus. amplification of coagulation cascade.
stabilization (via fibrin): platelet-platelet interaction. fibrin deposition

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12
Q

Step 1: vasoconstriction

including 3 things that can induce prothombotic endothelial changes

A

normally, vascular endothelium provides nonthrombogenic surface
damage to endothelium exposes the underlying extracellular matrix and elicits a contraction (vasoconstriction.)
-thrombin, hypoxia, and high fluid sheer stress can also induce prothrombotic endothelial changes

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13
Q

Step 2: formation of platelet plug

A

when platelets are exposed to the extracellular matrix in damaged endothelium they undergo a series of biochemical and physical alterations

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14
Q

3 major phases of the formation of a platelet plug

A

adhesion
activation
aggregation

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15
Q

platelets need to know

A

“thrombocytes”=thrombus/clot+cells
formed in bone marrow
normal concentration is 150,000-400,000 per microliter

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16
Q

life of a platelet

A

8-12 days

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17
Q

spontaneous bleeding and lethal platelet values

A

<50,000mcg/L spontaneous bleeding

<10,000mcg/L lethal

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18
Q

how is platelet adhesion allowed to happen

A

exposure to sub endothelial matrix proteins allows platelets to undergo a conformational change to adhere to the vascular wall. they become sticky.

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19
Q

von widebrand factor (vWF)

A

-produced in the endothelium and platelets.
-released by endothelial cells and by activated platelets. -its primary function is to bind other proteins. it is particularly important as a bridging molecule between the sub endothelial matrix and platelets forming a cross links.
glycoprotein IIb/IIIa
glycoprotein Ib/factor IX/factor V receptor complex

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20
Q

GP1b-V-IX complex

A

binds von wildebrand factor allowing platelet adhesion and platelet plug formation at sites of vascular injury. (absence of GP1b-V-IX receptor is known as bernard soulier syndrome)

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21
Q

when is von wildebrand factor mainly activated

A

in conditions of high blood flow and shear stress

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22
Q

where does vWF deficiency show and diagnosis

A

primarily in organs with small vessel such as skin GI and uterus.
diagnosed by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with binding assays. factor VIII is also measured

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23
Q

type 1 vWD (60-80%)

A

failure to secrete vWF into circulation or vWF being cleared more quickly than normal. mild, often undiagnosed until bleeding following surgery, easy bruising or menorrhagia
vWD is not secreted normally, give DDAVP

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24
Q

type 2 vWD (15-30%)

A

has to do with receptor binding sites.

qualitative defect and bleeding varies. decreased ability to bind to GPIb. decreased ability to bind VIII

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25
Q

type 3 vWD

A

need exogenous vWF. can’t give them DDAVP because they have no vWF to stimulate.
most severe, homozygous defective gene, complete absence of production of vWF. leads to extremely low levels of VIII since it does not exist to protect VIII from proteolytic degradation

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26
Q

platelet type aka pseudo vWD

A

defect of platelet GP1b receptor. vWF is normal, platelet receptor is abnormal. not vWF problem.

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27
Q

GPIIb/IIIa inhibitors MOA

A

blocks ability of fibrinogen to form around aggregated platelets. as a result, no fibrinogen bridging of platelets to other platelets can occur. blocks receptor on platelet for fibrinogen to bind

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28
Q

platelet activation

A

after platelets adhere to endothelial damaged wall, several intracellular signaling pathways are activated when ligands bind to platelet receptors and a series of physical and biochemical changes occur. also platelets develops pseudopod like membrane extensions to increase platelet surface area

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29
Q

platelet recruitment

A

platelets release granular contents resulting in recruitment and activation of additional platelets

30
Q

which meds do we used that are thromboxane A2 inhibitors

A

aspirin

naproxen

31
Q

aspirin MOA

A

inhibits ability of COX enzyme to synthesize precursors of thromboxane within platelets

32
Q

naproxen MOA

A

nonselective COX inhibitor

33
Q

ADP and platelets

A

P2Y12 receptors further amplify the response to ADP and draw forth the completion of aggregation

34
Q

receptors on a platelet include

A 
ADP (P2Y12)
TXA2 (TP)
Collagen (GP1A, GPVI)
vW factor (GP 1B-IX-V)
fibrinogen, vWF (GP IIb-IIIa)
35
Q

drugs that work for vWF abnormalities

A

glycoprotein IIb/IIIa- drug that works at receptor so vWF platelet can’t stick to it
glycoprotein Ib/factor IX/factor V receptor complex- prevents platelet adhesion to vessel wall

36
Q

what is always circulating with vWF

A

factor VIII

37
Q

GPIIb/IIIa inhibitor meds, t1/2 consideration, reversal, TW

A

abciximab (ReoPro) T1/2 12-24h
eptifibatide (Integrillin)
tirofiban (aggrastat)
-the last two have a short t1/2 so they are run at gtt’s
-not great reversals available, maybe can give platelets
-small therapeutic window

38
Q

ADP receptor antagonist prodrugs

A

ticlopidine (ticlid)
clopidogrel (plavix)
presugrel (defiant)
-these have to metabolize in the liver first to work

39
Q

ADP receptor antagonists-direct acting

A

ticagrelor (Brelinta)

cangrelor (Kengrexal)

40
Q

platelet aggregation

A

completes formation of platelet plug
activators released during activation phase recruit and amplify response of additional platelets to site of injury
newly activated glycoprotein IIb/IIIa receptors on the platelet surface bind fibrinogen to provide for cross linking with adjacent platelets. this is a covalent bond
-“fibrinogen is a net, it contracts and gets tight”

41
Q

3 formation of a blood clot

A

plasma and fibrinogen breaks down to produce fibrin, which subsequently becomes cross linked to a stable mesh.
coagulation factors are then activated and initiate coagulation cascade
soluble fibrinogen is converted to insoluble fibrin

42
Q

what is the key step in blood clotting

A

conversion of fibrinogen (I) to fibrin (Ia) by thrombin (IIa)

43
Q

what factor breaks clot down

A

plasminogen

44
Q

when is the intrinsic pathway activated

A

when blood contacts a negatively charged surface (ex exposed subendothelial collagen)

45
Q

when is the extrinsic pathway activated

A

when blood contacts cells outside the vascular endothelium. nonvascular cells express a membrane protein called tissue factor (III) which initiates this pathway

46
Q

where does the common final pathway begin

A

at factor X where extrinsic and intrinsic pathways meet

47
Q

which 4 factors are vitamin K dependent for utilization

A

II, VII, IX, X

2,7,9,10

48
Q

which coagulation factors are glycoproteins, not enxymes

A

vWF and tissue factor (III)

49
Q

where are most coagulation enzymes synthesized

A

liver

50
Q

which enzymes are not synthesized in liver

A

calcium (IV) comes from diet

vWF synthesized in endothelial cells and platelets

51
Q

common pathway of coagulation

A

common to both extrinsic and intrinsic
depicts thrombin generation and subsequent fibrin formation
prothrombin (II) is cleaved by activated factor X to produce thrombin (IIa)
signal amplification

52
Q

why does a CVA window exist

A

after a clot is formed, the actin and myosin of the platelets trapped in the fibrin mesh interact in a manner like that in muscle contraction. depicts clot strength.

53
Q
  1. Dissolution of Blood Clots
A

clot lysis occurs when plasminogen (normally found in the blood) is activated to plasmin

  • activation occurs by tissue plasminogen factor (t-PA) released from the tissue, vascular endothelium, plasma, and urine (urokinase)
  • plasmin is an enzyme (resembles trypsin in pancreatic secretions) which digests fibrin fibers, fibrinogen, factor V, factor CII, prothrombin, and factor XII
54
Q

tissue plasminogen activator

A

exogenous plasminogen activators such as streptokinase are used clinically to dissolve intravascular clots.

55
Q

thrombolytics

A

possess inherent fibrinolytic effects or enhances body fibrinolytic system by converting endogenous pro enzyme plasminogen to the fibrinolytic enzyme plasmin
-more capable of dissolving newly formed clots (platelet rick and weaker fibrinogen bonds).

56
Q

PT (prothrombin time)

A

evaluates extrinsic pathway. sample of blood plasma incubated with tissue factor in presence of excess Ca2+

57
Q

PTT (partial prothrombin time)

A

indicates performance of intrinsic pathway. sample of blood triggered by adding activator surface (silica) plus phospholipid and Ca2+

58
Q

ACT

A

performed by mixing whole blood with activated substance fo initiate activation of clotting cascade. widely used and reliable for high heparin concentrations. influenced by hypothermia, thrombocytopenia, coagulation deficiencies

59
Q 
viscoelastic testing 
thromboelastometry (TEG)
torsional thromboelastometry (ROTEM)
A

global assay for whole blood clotting including coagulation factors, inhibitors, anticoagulant drugs, platelets, fibrinolysis

60
Q

bleeding time

A

sensitive test of platelet function. time to bleeding stop recorded.

61
Q

heparin concentration measurements

A

increasing concentrations of protamine are added to samples of heparin containing blood. time to clot measured the sample in which heparin and protamine are most closely match will clot first

62
Q

platelet function tests

A

classic method involved centrifugation of patient blood to obtain platelet rich plasma, which is then analyzed in cuvette at 37c placed between light source and photocell

63
Q

bleeding time normal value

A

3-10min

64
Q

platelet count normal value

A

150-350,000mm^3

65
Q

PT normal value

A

12-14 seconds

66
Q

INR normal value

A

.9-1.2

67
Q

activated partial thromboplastin time (aPTT) normal value

A

25-35 seconds

68
Q

thrombin time (TT) normal value

A

<30 seconds

69
Q

activate coagulation time (ACT) normal value

A

80-150 seconds

70
Q

fibrinogen normal value

A

> 150mg/dL

Pharmacology N929 (11 decks)

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