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MLSCI 330 > Coagulation > Flashcards

Coagulation Flashcards

1
Q

What initiates primary hemostasis?

A

Exposure of subendothelial collagen following injury to the vessel wall

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2
Q

Anticoagulant properties of intact endothelium

A
  • prostacyclin (PLT inhibitor)
  • nitric oxide (vascular relaxing)
  • heparin sulfate
  • tissue factor pathway inhibitor (suppress extrinsic pathway)
  • tissue plasminogen activator (activate fibrinolysis)
  • smooth continuous surface (inert)
  • expression of endothelial protein C receptors (inactivates Va, VIIIa)
  • expression of cell membrane thrombomodulin
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3
Q

Pro-coagulant properties of damaged vasculature:

A
  • exposure of subendothelial connective tissue (collagen binds vWF and PLT)
  • vasoconstriction caused by harm
  • secretion of vWF from endothelial cells and regulation of PLT and leukocyte receptors
  • subendothelial cells (smooth muscle and fibroblasts contain tissue factor and FIII
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4
Q

This is a reversible process where pots binds to subendothelial collagen

A

Adhesion
- need vWF to promote or initiate activation

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5
Q

The bridge between PLT and collagen

A

VWF

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6
Q

When PLTs bind each other to form PLT plug

A

Aggregation
- blocks site of injury
- induced by ADP released from PLTs from adhesion

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7
Q

Function of ADP in aggregation

A
  • induces it
  • exposes fibrinogen receptor sites on the PLT membrane (GPIIb/IIIa)
  • up-regulates p-selection to surface of PLT = now PLT can absorb fibrinogen from plasma and aggregate with PLTs that have adhered to wall
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8
Q

T or F. Fibrinogen binding is a calcium-dependent process

A

T!

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9
Q

GPIIb/IIIa deficiency/calcium/ fibrinogen deficiency =

A

Defective platelet aggregation

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10
Q

granule secretion is simultaneous with this step

A

aggregation

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11
Q

which granules promote irreversible aggregation?

A

TxA2, ADP, thrombin

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12
Q

1st wave vs 2nd wave of granule secretion

A

1st wave = reversible, loose agg
2nd wave = stronger stimulus; irreversble

plug stabilized via fibrin

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13
Q

thromboxane A2 function

A

Ca2+ release
vasoconstriction
PLT agg

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14
Q

dense plt granules

A
  • fuse with plasma membrane to secrete contents
  • contains small molecules: ADP, ATP, Ca, Mgm serotonin
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15
Q

ADP

A

promotes agg
same with Ca and Mg

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16
Q

prolongs vasoconstriction

A

serotonin

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17
Q

alpha plt granules

A

secrete contents into surface-connected canalicular system that releases contents to external environment
- contains large molecules: PF4, PDGF, B thromboglobulin, endothelial GF, transforming GF, factors V, XI, vWF, fibronogen

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18
Q

Inactive form of an enzyme

A

Zymogen

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19
Q

Serine protease

A

Active form of clotting factor whose activity depend on the amino acid serine at activation site; serine proteases hydrolyze peptide bonds at specific cleavage site to convert the next factor into another serine protease

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20
Q

The Serine protease are…

A

Kallikrein
Factor IIa
VIIa
IXaa
Xa
XIa
XIIa
Plasminogen
Protein C

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21
Q

What does vit K do?

A

Catalyses the carbosylation of the amino-terminal glutamic acids
- carbonyl groups can then bind calcium and allow for the binding of platelet factor 3

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22
Q

Which coat factors are vitamin K dependent?

A

II (prothrombin)
VII
IX
X
Protein C, S, Z

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23
Q

These laces are particularly rich in tissue factor

A

Placenta, brain
Lungs
Thymus

TF = protein + phospholipid

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24
Q

What is PF3?

A

Membrane phospholipid on platelets
Becomes exposed when PLTs are activated
Catalytic surface; localized environment for activation of clotting factors

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25
Q

T or F. PT pathway is really slow

A

T! Will feedback and activate more of the PTT coat factors (does more of the work)

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26
Q

Role of vWF

A
  • carrier and stabilizes VIIIC
  • adhesion of PLTs to subendothelium
  • ristocetin agg of PLT
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27
Q

In-Vito hemostasis

A

TWO phases

  1. Initiation = on TF bearing cell; FCIIa + TF activates X and IX; Xa/Va activates small amounts of thrombin
  2. Propagation = large amts of thrombin on PLT; XIa binds activated PLT and IX -> IXa
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28
Q

Thrombin function

A

Activates PLT, Va, VIIIa, XIa, fibrinogen to fibrin

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29
Q

FVII does not just activate FX, it also activates…

A

IX and VIII

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30
Q

Without _____, FVIII is very labile

A

VWF

31
Q

Which factor dissociates FVIII from vWF

A

Thrombin

32
Q

Tenase complex

A

Active form of IX going to form more factor X; composed of FIX, VIII, PL on platelet surface

33
Q

Prothrombinase complex

A

FXa combines to form this; with FV and PL = creates a burst of thrombin = promotes feedback into loop

34
Q

Inhibitor and regulatory mechanisms of coagulation

A
  • fibrinolytic system
  • tissue factor pathway inhibitor
    Protein C system
    Anti-thrombin
  • protein Z-dependent protease inhibitor
35
Q

Components of the fibrinolytic system

A

Plasminogen
TPA
Urokinase
Plasminogen activator inhibitor 1
Alpha 2 anti plasmin
Thrombin-activatable fibrinolysis inhibitor

36
Q

Source of tpa

A

Damaged endothelial cells

37
Q

What is plasminogen

A

Breaks down fibrin polymers to FDPs
- can digest both fibrin and fibrinogen
- digests FV, FVIII
- causes 1st fibrinolysis
PREVENTED BY alpha-2-antiplasmin

38
Q

TPA function

A
  • binds plasminogen and initiates digestion
  • circulating TPA bound by inhibitors (PAI-1)
  • recombinant TPA used to dissolve clots
39
Q

Urokinase

A

Prevents clot formation in extra-renal collecting system
- incorpated into clot along w plasminogen & TPA
- activated in presence of fibrin and plasmin

40
Q

Plasminogen activator inhibitor 1

A
  • primary inhibitor of plasminogen activation
  • inactivates TPA and urokinase
  • prevents conversion of plasminogen to plasmin
  • present in excess of TPA, binds circulating TPA
41
Q

Alpha 2 anti-plasmin

A
  • 1ry inhibitor of free plasmin
  • rapidly and irreversibly binds free plasmin
    -slows down digestion of clot
42
Q

Primary inhibitor of plasminogen

A

PAI-1

43
Q

TAFI

A
  • thrombin-activatable fibrinolysis inhibitor
  • inhibits fibrinolysis by cleaving plasminogen/tPA binding sites on fibrin
  • prevent plasmin formation and fibrinolysis
44
Q

Marker of thrombosis and fibrinolysis

A

D-dimmers
-X-linked fibres cleaved by plasmin

45
Q

How can fragments inhibit hemostasis and contribute to hemorrhage?

A

It prevents PLT cit action and also hinders fibrin polymerization

46
Q

TFPI

A

TISSUE FACTOR PATHWAY INHIBITOR
- 80%% bound, rest circulates
- inhibits coagulation by inactivating FXa; binds FXa & inactivates TF:FVIIa
- protein S = co-factor
- TF pathway short-lived

47
Q

Protein C system

A
  • activated thrombin binds thrombomodulin (endothelial membrane protein)
  • thrombin + thrombomodulin = conformational change in thrombin = loses pro-coat properties
  • this complex activates protein C
  • APC combines with protein S
  • APC + PS = inactivates FVa, FVIIIa
  • APC promotes fibrinolysis (binds PAI-1)
48
Q

Anti-thrombin

A
  • inhibits FII, IX, X, XI, XII, Kallikrein, plasmin
  • activated by heparin from mast cell granules and hep. Sulfate on endo cells
  • therapeutic heparin increases activity of AT 1000x = potent inhibitor of coagulation
49
Q

Protein Z dependent protease inhibitor

A
  • inhibits FXa, FXIa (degrade)
  • binds cofactor protein Z and FXa with PL and Ca 2+
    = accelerated by heparin
  • vit K dependent!
50
Q

Bernard Soulier

A
  • aut recessive
  • allows binding of vWF to bring PLT closer to collagen
  • deficiency = adhesion problems
  • ristocetin induces this process that we can use for aggregation studies in vitro
51
Q

Bernard Soulier lab test results

A
  • normal PT/PTT
  • n to increased PLTs
  • bleeding time increased
  • PLT agg studies
    > neg with ristocetin
    > decreased w thrombin
    > N w ADP, epi, collagen (don’t use GPIb)
52
Q

Glanzman’s Thrombasthenia

A
  • aut recessive
  • GPIIb/IIIa allows fibrinogen to cross link PLT
  • deficiency of the receptor leads to defective aggregation and bleeding issues
53
Q

Glanzman’s lab test results

A
  • normal PT/PTT and PLT #
  • increased bleeding time
  • PLT agg studies = normal with ristocetin only; neg with all other
54
Q

Method to study dense granules

A
  • electron microscopy
  • genetic studies
55
Q

Dense granule deficiency

A
  • non-albinism = granule membrane there but no condense; inability to package; mild bleeding; PLT agg = prolonged
  • albinism = Chediak Higashi; profound granule def; no response
56
Q

Alpha granule deficiency

A
  • auto recessive
  • agranular appearance (can see in PBS)
  • grey PLT syndrome
  • prolonged BT and decreased PLT count and slightly larger in size
57
Q

VWF disease

A
  • autosomal dominant
  • mutations in vWF gene (qual or quant)
  • bleeding probs due to abnormal PLT adhesion
  • usually accompanied by FVIII:c deficiency
  • disease severity varies (depending on homogeneity)
  • bleeding usually mucocutaneous (easy bruising, nosebleeds, etc.)
  • less vWF = type O blood
58
Q

VWF disease usually accompanied by a deficiency in

A

Factor VIII

59
Q

VWF disease lab test results

A
  • PLT agg = ristocetin variable and others = normal
  • PT/PTT = N; PTT may be increased
  • PLT - N
  • BT = prolonged
  • ristocetin co-factor assay = no aggregation
60
Q

Treatment for vWF disease

A

Desmopressin
- triggers release of vWF from endothelial cells or give recombinant vWF

61
Q

Hemophilia A

A
  • F8 def
  • X-linked recessive
  • may have Abs to FVIII or FVIII:c
  • PTT prolonged; TT = normal; inhibitor screen may be abnormal; BT = normal
  • FVIII assay to tell severity of disease
62
Q

F9 deficiency

A

Hemophilia B
- X-linked recessive
- Christmas
- prolonged PTT
- normal BT and TT

63
Q

F11 def

A

Hemophilia C
- aut dominant
- prolonged PTT
- normal BT, TT
- inhibitors = normal

64
Q

FV Leiden mutation

A
  • aut dom thrmobophilia
  • single pt mutation that removes APC binding site on FV (APC cannot inactivate it) = thrombosis/increased clots
  • clot-based assay to screen; DNA/genetic studies for confirmation
65
Q

Prothrombin G20210A

A
  • inherited thrombophilia
  • elevated plasma prothrombin concentration
  • increase rick of thrombosis
  • DNA/genetic studies/PCR to diagnose
66
Q

Acquired thrombotic disorder - lupus anticoagulant/antiphospholipid

A
  • non-specific inhibitor
  • binds protein-phospholipid complex in PTT reagent
  • no- in-vivo effects
  • patients prone to stroke and DVT
  • everything prolonged; but viper venom normal and mixing studies no correction
67
Q

Causes of a quad factor deficiencies

A
  • liver disease
  • vit. K deficiency = no carboxylation and activation
  • autoantibodies = inhibits action of coat factors ; FVIII most common (SLE, pregnancy, idiopathic, etc.)

NOTE -results not corrected in mixing studies ; corrected using diluted samples which dilute out inhibitor activity

68
Q

Treatment for autoantibodies

A

Immunosuppressants

69
Q

Sample requirements

A
  • sodium citrate
  • filled to capacity
  • 1:9 anticoag:sample
  • do not heat or freeze
  • can freeze plasma
70
Q

Benefits of sodium citrate

A
  • preserves V, VIII
  • stabilizes pH
  • does not inhibit PLT function
  • easily reversed with calcium
71
Q

Why isn’t EDTA used in coat testing

A
  • does not preserve FV
  • interferes with fibrin polymerization
72
Q

Why isn’t heparin used in coag testing

A
  • activates anti-thrombin
  • prolongs results
73
Q

Normal results in D-dimmer testing rules out…

A

DIC, DVT, PE

MLSCI 330 (9 decks)

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