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Coagulation > Coagulation Pathway and Physiology > Flashcards

Coagulation Pathway and Physiology Flashcards

1
Q

Heparin Sulfate

A

-glycosaminoglycan -attached to the luminal surface of the endothelium -acts as a cofactor for Antithrombin (main direct inhibitor of many coagulation factors)

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2
Q

Antithrombin

A

-serine protease inhibitor -5 stranded central beta-sheet (A-sheet) -conformational changes by binding of Heparin to arginine residues increases inhibition effect of antithrombin by 1000 fold (exposes the reactive center)

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3
Q

Platelets

A
  • discoid, anucleate fragments that can be up to 3 microns in size - complex structure including actin and myosin filaments
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4
Q

Zymogen forms of Vitamin K dependent serine proteases

A

-Factors II, VII, IX, and X -Proteins C, S, and Z

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5
Q

Why is Vitamin K so important for these dependent factors?

A

-It is necessary cofactor for post-translational modification that adds a carboxyl group to 10-12 glutamic acid residues in the amino terminal portion of the factors and proteins -The factors and proteins utilize this addition to adhere to adhere to phospholipid membranes and assemble multimolecular coagulation complexes -Without this happening there is ineffective fibrin formation

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6
Q

How does Warfarin affect this system?

A

-inhibits the carboxyl addition to the glutamic acid -this effect is monitored by the clot-based PT assay

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7
Q

Fibrinogen (Factor I)

A

-Adhesive protein that forms the fibrin clot

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8
Q

Prothrombin (Factor II)

A

-vitamin K dependent -activated form is main enzyme of coagulation

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9
Q

Tissue Factor (Factor III)

A

-Lipoprotein initiator of extrinsic pathway

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10
Q

Calcium ions (Factor IV)

A

-necessary for all reactions -metal cation

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11
Q

Factor V (Labile factor)

A

-Cofactor for activation of prothrombin to thrombin

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12
Q

Factor VII (Proconvertin)

A

-Vitamin K dependent -With Tissue Factor, initiates the intrinsic pathway

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13
Q

Factor VIII (Antihemophilic Factor)

A

-Cofactor for intrinsic activation of Factor X

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14
Q

Factor IX (Christmas Factor)

A

-Vitamin K dependent factor -Activated form is enzyme for intrinsic activation of Factor X

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15
Q

Factor X (Stuart-Power Factor)

A

-Vitamin K dependent factor -Activated form is enzyme for final common pathway activation of prothrombin

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16
Q

Factor XI (Plasma thromboplastin antecedent)

A

-serine protease -Activated form is intrinsic activator of Factor IX

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17
Q

Factor XII (Hageman Factor)

A

-Serine protease -Factor that nominally start aPTT-based intrinsic pathway

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18
Q

Factor XII (Fibrin-stabilizing factor)

A

-Transamidase that cross-links fibrin clot

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19
Q

Prekallikrein (Fletcher factor)

A

-Serine protease -Activated form that participates at beginning of aPTT-based intrinsic pathway

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20
Q

PT is a measure of which pathway?

A

-Extrinsic pathway (Tissue factor and Factor VII)

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21
Q

aPTT is a measure of which pathway?

A

-Intrinsic pathway

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22
Q

History suggestive of vWD bleeding

A

-Menorrhagia -Bleeding from minor wounds -Surgical bleeding -tooth extraction -epistaxis

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23
Q

History suggestive of non vWD related bleeding

A

-postpartum hemorrhage -oral and GI bleeding -hemarthrosis -hematomas -CNS bleeding

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24
Q

Blue top tube

A

-Citrate anticoagulant -Use for: PT, PTT, TT, Fibrinogen, XDP, FDP, Factor assays, thrombosis assays, and vWD assays

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25
Q

Purple top tube

A

-used for CBC and platelet counts

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26
Q

PT (Extrinsic pathway) what it is sensitive to

A

-7, 10, 5, 2, Fibrinogen

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27
Q

What conditions prolong PT

A

-Warfarin therapy or Vitamin K deficiency -Liver disease -Acquired or hereditary deficiency of any of the factors (7, 10, 5, 2, and Fibrinogen) -Factor or assay inhibitors (drugs, antibodies)

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28
Q

aPTT (Intrinsic pathway) what it is sensitive to

A

-8, 9, 10, 11, 5, 2, Fibrinogen, Heparin

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29
Q

aPTT is prolonged in what conditions

A

-Heparin therapy or sample contamination (Hep lock, IV line) -Lupus anticoagulant -Hereditary or acquired deficiency (hemophilia) -Severe liver disease -Factor or assay inhibitors (drugs, antibodies) -Contact system deficiency (not associated with bleeding) –> Factor 12, HMWK, Pre-Kallikrein

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30
Q

Thrombin time (TT) sensitive to

A

-Final step, fibrinogen -Heparin and fibrinogen

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31
Q

TT prolonged in what conditions

A

-Heparin therapy or contamination -Severe fibrin(ogen) degradation (DIC) -Dysfibrinogen -Thrombin inhibitor (Leperudin, drugs, antibodies)

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32
Q

Fibrinogen assay

A

-kinetic method of Clauss -sensitive to Fibrinogen

33
Q

Cross-linked fibrin degradation products (D-dimer)

A

-assay is a quantitative latex immunoassay (rapid and available stat)

34
Q

D-dimer is increased in what conditions

A

-Thrombosis (DVT, PE, extensive arterial thrombosis) IMP: quantitative NPV >95% for PE and proximal DVT -DIC (>8 ug/mL suggests DIC) -Thrombolytic therapy

35
Q

Platelet count

A

-assay: automated cell counter

36
Q

Platelet count is decreased in

A

-Leukemia and cancer therapy -ITP, TTP

37
Q

Platelet function screen (assay)

A

-platelet function analyzer -whole blood is drawn through a collagen-epinephrine or collagen-ADP coated orifice -measure the time of occlusion of the orifice

38
Q

What increases the platelet function assay time/screen

A

-Thrombocytopenia -Anemia -Antiplatelet drugs -vWD -other hereditary and acquired platelet dysfunction

39
Q

Thromboelastograph (TEG)

A

-assay: measurement of elastic shear modules (ESM) of whole blood as it clots (5 indices) -R= time to clot onset -K= time to 2 cm ESM amplitude -Angle = angle from clot onset tangential to ESM curve -Maximum amplitude = Maximum ESM -Lysis % = % drop amplitude at the end from fibrinolysis

40
Q

TEG sensitive to the following

A

-platelet count -coag factors -fibrinogen -fibrinolysis

41
Q

Antithrombin activity

A

-assay: chromogenic substrate anti-IIa asay -Thrombin is Factor IIa -plasma is diluted in heparin buffer, excess thrombin is added -AT/Hep complex binds to and inhibits thrombin -Residual thrombin is measure with chromogenic substrate -Difference orginal-final thrombin equals AT activity

42
Q

Antithrombin activity is decreased in what conditions

A

-Heparin therapy -ongoing extensive thrombosis -systemic coagulation activation (DIC) -Nephrotic syndrome -Hereditary deficiency -Asparaginase therapy

43
Q

Protein C activity (assay)

A

-Chromogenic assay, plasma diluted in buffer -snake venom Protein C activator is added -Protein C activity is measured with chromogenic substrate -measures carboxylated and non-carboxylated protein C molecules

44
Q

Protein C activity is decreased in what conditions

A

-Warfarin therapy -Vitamin K deficiency -Liver disease -Ongoing extensive thrombosis -systemic coagulation activation (DIC) -Hereditary deficiency

45
Q

Protein S (assay)

A

-Free protein S antigen (preferred screening assay) quantitative latex immunoassay (LIA test) -Protein S activity -conditions affecting this assay: interference from elevated levels of Factor VIII (false low) thrombin inhibitors (false high, Lepirudin)

46
Q

Free protein S antigen and Protein S activity decreased in what conditions

A

-Warfarin therapy -Vitamin K deficiency -Liver disease -Ongoing or extensive thrombosis -systemic coagulation activation (DIC) -Pregnancy -Inflammatory syndromes with increase C4B binding protein -Hereditary deficiency

47
Q

Lupus inhibitor assay (statclot assay)

A

-assay: lupus sensitive PTT with and without addition of excess hexagonal phase phospholipid -calculate the difference in clotting time with and without hexagonal phospholipid

48
Q

Activated Protein C resistance

A

-PT based assay -Factor V activation and inhibition by APC -calculate the ratio with and without APC added -Reduced ratio indicates APC resistance–> Factor V leiden

49
Q

von Willebrand Factor Antigen

A

-assay: quantitative automated latex immunoassay

50
Q

von Willebrand Factor Function

A

-assay: enzyme immunoassay- antibody directed to functional site on vWF -highly correlated with Ristocetin cofactor assay -Type 1: reduction in parallel with vWF antigen -Type 2: greater reduction than vWF antigen

51
Q

Collagen binding- vWF function

A

-assay: collagen coated plate, plasma vWF binds to collagen, bound vWF detected with anti-vWF antibody -Type 1: reduction in parallel with vWF antigen -Type 2: greater reduction than vWF antigen

52
Q

von Willebrand Factor Multimers

A

-assay: Western Blot of von Willebrand Factor -Type 2A: loss of intermediate and high MW multimers, abnormal forms -Type 2B: loss of high MW multimers, normal pattern

53
Q

Factor VIII Activity

A

-assay: clot based single stage assay

54
Q

What is primary hemostasis ?

A
  • Formation of the platelet plus
55
Q

What is secondary hemostasis ?

A
  • activation of the coagulation proteins
56
Q

What is the role of endothelium in the

coagulation process?

A
  • physical barrier with pro-coagulant properties when the wall is breached
  • subendothelial matrix proteins:
    • fibronectin
    • collagen
    • thrombospondin
    • cause platlet adhesion
  • Adventitia of vessel contains Tissue Factor
    • activates the extrinsic pathway of the Coagulation cascade
57
Q

What is Tissue Factor and what is its role in coagulation ?

A
  • intrinsic membrane protein
  • constituitively expressed on the plasma membrane of adventitial cells of vessel
  • activates Extrinsic Pathway
  • must be activated by endothelial injury, not normally present in active form
58
Q

What are the prothrombotic properties of the endothelium ?

A
  • major synthetic and storage site for von Willebrand factor
  • protects sites of injury from pre-mature fibrinolysis
    • Thrombin-activatable fibrinolysis inhibitor
    • Plasminogen Activator inhibitor-1 (PAI-1)
59
Q

What is von Willebrand Factor ?

A
  • large multimeric protein that acts as the intercellular glue binding platelets to one another and to the subendothelial matrix at the site of injury
  • during synthesis in the endothelium large monomers are dimerized
    • they become large multimers of various lengths
    • before storage and secretion: vWF propeptides are cleaved from the multimers
    • VWF multmers are stored in Weibel Palade bodies along with ADAMTS13
60
Q

How does VWF lead to formation of a clot?

A
  • Note: major role in platelet function as well as carrier protein for Factor VIII
  • secreted as ultra-large vWF multimers that are stretched out by shear stress and remain anchored to the endothelium
    • have increased platelet binding activity
    • require cleavage by ADAMTS13 to prevent pathologic platelet thrombi
      • cleaves at specific sites
      • creates shorter multimers that form globular structures
61
Q

What is the role of Thrombin-activatable fibrinolysis inhibitor (TAFI)

in thrombosis ?

A
  • a protein that is found on the endothelium that promotes thrombosis
  • protects from premature clot dissolution at the site of injury
  • cleaved to its active form by Thrombin-Thrombomodulin complex
    • Thrombomodulin is found on the endothelial surface
    • only known ligand of Thrombin
    • when bound to thrombomodulin, thrombin activity focuses on TAFI
  • TAFI catalyzes the removal of lysine residues from the fibrin clot
    • becomes less recognizeable as a substrate for plasmin
    • so the clot persists
62
Q

What is the role of plasminogen activator inhibitor type I

(PAI-1) in promoting thrombosis ?

A
  • PAI-1 is produced by the endothelium and is only activated by inflammatory cytokines in this setting
    • other sources: platelets, adipose tissue and liver
  • PAI-1 blocks the activity of plasminogen to activate plasmin
    • plasmin is the primary enzyme of fibrinolysis
63
Q

What are the antithrombotic properties of

the endothelium ?

A
  • Secretion of tissue factor pathway inhibitor
  • assembly of the protein C activation complex
    • via thrombomodulin and endothelial protein C receptor
  • acceleration of antithrombin activity on the endothelial survace by Heparin sulfate
  • secretion of prostacyclin and nitric oxide
  • secretion of tissue plasminogen activator
64
Q

How does activated protein C downregulate

the formation of thrombin ?

A
  • activated protein C causes proteolysis of Factor Va and VIIIa to prevent the formation of thrombin.
65
Q

How does Heparin-sulfate contribute to

thrombin degeneration ?

A
  • Heparin sulfate is a cofactor for antithrombin
    • this is one of the main inhibitors of coagulation enzymes
  • Note: the thrombin-antithrombin complex is removed by hepatocytes from circulation
66
Q

How are platelets inactivated by the endothelium

to prevent thrombosis ?

A
  • by production of PGI2 (prostacyclin) and NO (nitric oxide)
    • release of mediators induced by excess thrombin from adjacent vessel injury
    • thrombin binds and activates protease activated receptor type 1 (PAR-1)
      • activates G coupled proteins
      • causes production of PGI2 and NO
      • both are potent platelet inhibitors
67
Q

Where is tissue plasminogen activator (tPA) secreted from ?

A
  • endothelium
  • main enzymatic activator of the potent fibrinolyitic plasmin
  • resting endothelium secretes tPA at low levels
68
Q

What are the Vitamin K dependent factors

and what enzyme is key in their production ?

A
  • Factors II, VII, IX, X, proteins C and S
    • zymogen forms of Vitamin K dependent serine proteases
  • modification occurs via: Gamma Glutamyl Carboxylase
    • adds a carboxyl group to the proteins
    • allows the proteins to adhere to phospholipid surfaces and assemble macromolecular coagulation complexes
69
Q

What is the enzyme that Warfarin intereferes with ?

A
  • Vitamin K Epoxide reductase
  • interferes with the recycling of reduced Vitamin K
  • Note: dietary or medicinal Vitamin K bypasses Warfarin
70
Q

Why are newborns susceptible to Vitamin K deficiency ?

A
  • lack the acquired GI flora responsible for the production of Vitamin K
71
Q

What enzymatic variations are most common in

the individual variation in response to Warfarin ?

A
  • VKORC1 - vitamin K epoxide reductase 1
  • CYP2C9 (responsible for breakdown of Warfarin)
72
Q

What two factors are not essential to the

Coagulation cascade ?

A
  • Factor XII and prekallikrein
73
Q

In vivo, where is tissue factor normally seen?

A
  • constituitively present on adventitial fibroblasts
  • induced expression seen on monocytes or endothelial cells
    • these can deliver Tissue factor to sites of injury
74
Q

What molecule is the sole amplifier of the

coagulation cascade ?

A
  • Thrombin
    • greatest instigator of clot formation and maintenance (thrombin burst)
  • Amplifies the intrinsic pathway via:
    • Factor XI
    • Factor V
    • Factor VIII
  • Thrombin also affects:
    • coagulation proteins, platelets and endothelial cells
75
Q

What are some other functions of Thrombin ?

A
  • converts fibrinogen to fibrin
  • activates Factors XI, V, VIII and XIII
  • activates protein C on the endothelium (inhibits coagulation)
  • activates protease-activated receptor type I (PAR-1) on endothelium
    • promotes fibrinolysis and blocks platelet activation
  • activates TAFI on endothelium
    • inhibits fibrinolysis
  • activates PAR-1 and PAR-4 on platelets
    • promotes platelet activation
76
Q

What are the normal levels of Protein S,

what affects those levels, and what other regulatory process

is protein S involved in ?

A
  • Functional protein S levels are normally around 40% circulating free in plasma
    • 60% is bound to complement inhibitor protein, C4b
      • C4b binding protein increases in pregnancy and acute phase reponses
      • can decrease the fraction of free protein S
  • Protein S also a cofactor
    • inhibition of factor Xa by TFPI
77
Q

What is the role of Antithrombin ?

A
  • major serpin anticoagulant
  • protease inhibitor produced in the liver
  • has a Heparan binding helix
    • inhibition is accelerated 1000 fold by binding of heparin to argining residues
  • IMP: inhibition is not limited to thrombin
    • also factor Xa, IXa, XIa and VIIa
    • protease gets covalently bound to antithrombin once trapped
78
Q

What is the role of Heparin cofactor II ?

A
  • serpin with activity against thrombin
  • produced in the liver, specific only to thrombin and not other factors
  • 40% of it colocalizes to extravascular tissues

Coagulation (17 decks)

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