Nomenclature And Intro To Coag Cascade Flashcards by Arriane Cyrel (MTI)

Complex molecule in the plasma

VIlI/vWF

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: coagulation

VIII: C

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: platelet adhesion

VIII:vWF

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Produced as a big complex

VIlI/vWF

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Platelet adhesion

VIlI:vWF

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tested by BT

VIlI:vWF

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acts as an adhesive to the endothelium

VIlI:vWF

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can be tested by bleeding time when deficient

VIlI:vWF

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prolonged bleeding time may be caused by VWF due to defect in plt adhesion

VIlI:vWF

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Starts to separate when matures in the endothelium ([?] moves to the circulation; [?] remains in the endothelium)

FVIII

VWF

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cofactor (FIX+Ca)

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tested by PTT

VIII:C

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VIII:C APTT:

Intrinsic

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VIII:C PT:

extrinsic

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individual factor

VIII:C

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seen in the coagulation cascade

VIII:C

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“C” for

cofactor or coagulant portion of factor VIII

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Serves as a cofactor to Factor IX and Calcium (needed to activate FX in the common pathway)

VIII:C

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part of “intrinsic prothrombinase”

VIII:C

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Antigenic property of VIII:C

VIIIC:Ag

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Tested by monoclonal antibody (antisera)

VIIIC:Ag

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FVIII may have an inhibitor and attacks FVIII

VIIIC:Ag

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Antigenic property of vWF

VIIIR:Ag

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tested by Laurell rocket

VIIIR:Ag

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low VWF FVIII Ag : low VWF = prolonged bleeding

VIIIR:Ag

Ristocetin cofactor

VIIIR:RCo

required for plt aggregation

VIIIR:RCo

tested during in vitro aggregation

VIIIR:RCo

different factors seen in the circulation

Coagulation Factors

Coagulation Factors Synthesis:

LIVER

A. Zymogens → serine proteases Factors:

II, VII, IX, X, XI, XII, and PK

A. Zymogens → serine proteases Exemption:

FXIII, FVIII:C

B. Zymogens → cofactors Factors:

V, VIII, TF, HMWK + Thrombospondin & Protein C and Protein S

C. Factor deficiency → abnormal hemostasis Factors:

All factors except: FXII,PK,HK

Labile factors Factors:

I, V, VIII,VII, IX, X

: produced from the sinusoids of endothelium/lining of blood of the liver, along w/ FVIII:VWF)

FVIII:C

: blood island-like in the endothelium, which are tissues that produced VWF (specifically) with FVIII complex

Weibel Palade bodies

: transaminase from monocyte, macrophage, reticuloendothelial cell (eliminates foreign bodies)

FXIII

: cofactor for plt function

Thrombospondin

helps fibrinolytic factors and act as cofactors for plasmin in fibrinolysis

Protein C and Protein S

can control activation of factor V, II, IX

Protein C and Protein S

inhibits coag factors to enhance fibrinolysis

Protein C and Protein S

cofactors for fibrinolysis

Protein C and Protein S

in vivo

FXII,PK,HK

can still activate FX

FVII (extrinsic factor)

Ex. deficiency in [?] will not cause prolonged APTT

Contact factor (XII)

Disappears in the body in the presence of other substances

I, V, VIII,VII, IX, X

Ex. [?] disappears in the presence of couamarin/heparin (can only use FXII)

FVII

Ex. [?] are labile factors outside the body and disappears upon exposure to low temperature

FV, FVIII, FIX, FI, FX

Other cells that produces coagulation factors aside from the liver:

Monocyte, Macrophage, Reticuloendothelial cell + Megakaryocyte + Tissue factor (FIII)

cells that participate in coagulation except for plt

Monocyte, Macrophage, Reticuloendothelial cell + Megakaryocyte

produces FXIII

Monocyte, Macrophage, Reticuloendothelial cell + Megakaryocyte

slightly procoagulant: induces coagulation (during bleeding, they increase in number and participate in clotting)

Monocyte, Macrophage, Reticuloendothelial cell + Megakaryocyte

- originates from the bm

megakaryocyte

- does not exist for long due to short lifespan

megakaryocyte

- will release some cag factors if not shedded into platelet

megakaryocyte

Activates FVII to become FVIIa

Tissue factor (FIII)

originated from fibroblasts and smooth muscles

Tissue factor (FIII)

13 coagulation factors are divided to

three groups

FIBRINOGEN Heat labile: [?] (disappears when heated above 37C)

I,V,VIII

FIBRINOGEN Storage labile:

V,VIII

PROTHROMBIN Heat labile: [?] (disappears when heated above 37C) (Except [?] – consumed)

VII,IX,X FII

PROTHROMBIN Storage:

well preserved (most stable)

CONTACT Storage:

fairly stable

Vit K Dependent

PROTHROMBIN

Not Vit K Dependent

FIBRINOGEN CONTACT

Adsorbed by Ba04 and Al(OH)3

PROTHROMBIN

Adsorbed by Ba04 and Al(OH)3

FIBRINOGEN CONTACT

Consumed in coagulation

FIBRINOGEN

Not Consumed in coagulation

Prothrombin (Except FII)

Partially Consumed in coagulation

CONTACT

Site FIBRINOGEN

Plasma

Site PROTHROMBIN

Plasma/Serum (Except FII)

Site CONTACT

Plasma/Serum

Destroyed by Plasmin/High thrombin level

FIBRINOGEN

Also destroyed by high/deactivated level of thrombin

FIBRINOGEN

Found in plt

FIBRINOGEN I, V, VIIIR:Ag Cytoplasm: XIII

Acute Phase Reactant (participates in inflammation)

FIBRINOGEN

Reduced by oral anticoag (heparin, warfarin, Coumarin)

PROTHROMBIN

FIBRINOGEN GROUP:

Factors I, V, VIII, XIII

PROTHROMBN GROUP (VITAMIN K- DEPENDENT GROUP):

Factors II, VII, IX, X

CONTACT GROUP:

Factors XI, XII, Prekallikrein, HMWK

Large molecules

FIBRINOGEN GROUP

Substrate for plasmin

FIBRINOGEN GROUP

consumed during coagulation

FIBRINOGEN GROUP

most labile

FIBRINOGEN GROUP

FIBRINOGEN GROUP increased in:

1. Inflammation 2. Pregnancy 3. Use of contraceptive pills

Not dependent on Vit K

FIBRINOGEN GROUP CONTACT GROUP

Vitamin K dependent factors (group)

PROTHROMBN GROUP

not consumed during coagulation

PROTHROMBN GROUP CONTACT GROUP

stable (stored plasma)

PROTHROMBN GROUP

requires Ca++ as a cofactor in binding to plt phospholipid

PROTHROMBN GROUP

PROTHROMBN GROUP Decreased in:

1. Oral anticoagulants (function) 2. GIT absorption problems

CONTACT GROUP

Fairly stable

CONTACT GROUP

activation: negatively charged

CONTACT GROUP

related to fibrinolytic kinin and complement system

CONTACT GROUP

targeted by plasmin during fibrinolysis

Factors I, V, VIII, XIII

has the most cf in the clot – attack these 4 to dissolve the clot

Factors I, V, VIII, XIII

is converted to fibrin, forming the fibrin clot

FI (fibrinogen)

is a cofactor in common pathway

is a cofactor in intrinsic pathway

FVIII

is a stabilizing factor

FXIII

Target the cofactors, largest substrate, and stabilizing factor to stop the coagulation and make the clot very soft

Factors I, V, VIII, XIII

are affected by temperature

FV and VIII

affected by temperature Except for [?] (does not activate and disappears in the presence of anticoagulant)

FXIII

Congenital hemmorhage (Vit K deficiency)

Factors II, VII, IX, X

Remains as zymogens w/o Vit K

Factors II, VII, IX, X

: only activates fibrinogen and fibrin (not particularly present in the clot; only activators)

FII (thrombin)

: only activates FX (not particularly present in the clot; only activators; alr consumed during the coagulation cascade and not in the clot itself)

FVII and FIX

: substrate inactivated needed to activate FI

These can go back to the circulation and be reactivated again

Factors II, VII, IX, X

These can go back to the circulation and be reactivated again Except [?]

FII

not included in the cf because it only activates the fibrin clot

FII

also functions in platelets by strengthening plt function

FII

plays a role in plt plug formation, thus consumed

FII

: requires Ca and plt phospholipid (PPL)

FII, FVII, IX, X

FVIII, FIX + Ca + PPL

: not a coagulation factor, but only a plt

PPL

Steps in coagulation with participation of platelet

FVIII, FIX + Ca + PPL

: used to control thrombosis in the body (DVT)

Coumarin, Heparin

: can cause obstruction of blood vessel, leading to rupture of vein and increased blood pressure, affecting the heart; blood will not clot

deep vein thrombosis or DVT

: caused by anticoagulant called warfarin

PIVKA (Protein in Vitamin K Antagonism)

proteins become antagonistic to Vit K

PIVKA (Protein in Vitamin K Antagonism)

Effect: loss of Vit K and coag factors & Ca (cofactor) cannot bind w/ coag factors

PIVKA (Protein in Vitamin K Antagonism)

inactivation of Factors II, VII, IX, X + Ca

PIVKA (Protein in Vitamin K Antagonism)

Ulcerations, pernicious anemia (inability to absorb and breakdown due to stomach acid)

Factors II, VII, IX, X

Vit K will not be absorbed if there is an absorption problem (ex. Carrot will only pass thru the body)

Factors II, VII, IX, X

they are just contact factors (first to feel if clot is needed)

It will take time to disappear after storage

XI, XII, PK, HK

Not as stable as Prothrombin group

CONTACT GROUP

injury to endothelium: [?] is exposed to Collagen

FXII

Collagen: from injured endothelium that gives off negatively charged surface, which will activate

FXII to FXIIa and FI to FIa

: no role in coagulation but can amplify the action of FXII and FXI

PK and HK

related to fibrinolytic kinin and complement system specifically

PK and HK

When isolating a coagulation factor present in a clot, these two are used to extract and elute the coag factors

BaSO4 (Barium Sulfate) or Al(OH)3 (Aluminium Hydroxide)

: cannot be adsorbed by BaSO4 or Al(OH)3

Fibrinogen group and Contact group

: can be adsorbed by BaSO4 or Al(OH)3

Prothrombin group

Clot in BaSO4: : prothrombin group and other coag factors : fibrinogen group and contact group (very adhesive to the glass surface)

- extracted/eluted - left in the clot/system

inhibits coagulation factors

Regulatory proteins

enhances fibrinolysis

Regulatory proteins

Regulatory proteins:

Protein C, Protein S Protein Z

: inihibits FV and FVIII

Protein C, Protein S

3 THEORIES ON COAGULATION

1. Morawitz/Classical Theory (1905) 2. Howell's theory (1910) 3. Modern theories: “Waterfall” & “Cascade” (1964)

: generate fibrin clot to stop bleeding

COAGULATION

system addressed to arrest bleeding by fibrin formation

COAGULATION

: step by step formation of proteins to generate thrombin and fibrin

CASCADE

Morawitz/Classical Theory (1905) • believes that there are 2 stages coagulation:

1. thrombin formation 2. fibrin formation

thrombin formation: by the combination of

prothrombin (inactive form) + calcium ions + tissue thrombokinase (tissue factor) = generation of thrombin

: activators

Ca and Thrombokinase

known activator:

TF (from damaged endothelium) and Ca+

fibrin formation: the formed [?] acts on the [?] in the plasma

thrombin fibrinogen

Prothrombin + thrombokinase ——-(Ca)——->

thrombin

Thrombin + Fibrinoen ———>

Fibrin

Howell's theory (1910) • This theory believed that there are 5 coagulation factors involved:

(Fibrinogen, Calcium, Prothrombin, Anti-prothrombin, Thromboplastin)

: most common therapeutic circulating antiprothrobin

heparin

Anti-prothrombin 2 steps: to target

1) thrombin (inactivation back to prothrombin) 2) prothrombin (not allowed to be activated to thrombin)

Address the circulating anticoagulant to allow thrombin to activate fibrin

Anti-prothrombin

Thrombin activates fibrinogen to become fibrin

Anti-prothrombin

Anti-prothrombin • Sequence of reactions: a. [?] is inactivated by antiprothrombin/heparin b. [?] neutralizes antiprothrombin and releases prothrombin

Prothrombin Thromboplastin (thrombokinase or TF)

Activation of factor X via the intrinsic or extrinsic pathway

Modern theories: “Waterfall” & “Cascade” (1964)

Conversion of prothrombin to thrombin

Modern theories: “Waterfall” & “Cascade” (1964)

• Conversion of fibrinogen to fibrin

Modern theories: “Waterfall” & “Cascade” (1964)

• Advocated the phases of coagulation

Modern theories: “Waterfall” & “Cascade” (1964)

PHASES of Coagulation

1. Contact Phase 2. Activation of Factor X 3. Conversion of Prothrombin to Thrombin 4. Formation of fibrin

- Starts with the activation XII, then activation of prekallikrein and factor XI.

1. Contact Phase

via Intrinsic Pathway or via Extrinsic Pathway

2. Activation of Factor X

THE COAGULATION CASCADE

1. INTRINSIC System 2. EXTRINSIC System / TISSUE FACTOR Pathway 3. COMMON Pathway

All components are found in the [?]. To be activated, the blood must have [?] with a foreign object such as a [?].

circulating blood direct contact damaged blood vessel or glass

This results to absorption of [?] to the [?] exposed by vessel wall damage.

XII negatively- charged collagen

1. INTRINSIC System • Sequence of reactions: 1. Factor [?] is activated by the foreign material into [?] 2. [?] reacts weakly with [?], thus converting them into their forms 3. [?] in the presence of Ca++ activates [?] 4. [?] in the presence of Ca++, platelet phospholipids, and Villa activates [?].

XII; XIIa XIIa; XI, prekallikrein (also by XIIf), and plasminogen Xla; Ca++; IX IXa; X

Formed [?] feeds back to [?] and causes enzymatic cleavage producing more [?].

kallikrein XIl Xlla

Note: [?] can also be activated by [?]: (CURRENT CONCEPT OF COAGULATION)

IX VIIa-Ca++-TF complex

is necessary for the activation of EXTRINSIC system

TISSUE FACTOR

All cells with the possible exception of those in the blood, contain [?].

tissue factor

When injury occurs, the [?] is released and acts as a cofactor in initiating coagulation.

tissue factor

The released tissue factor binds to [?] and activates it to [?].

VII VIla

Then VIla, together with calcium, activates [?] to [?] of the common pathway.

X Xa

COMMON Pathway Begins with activation of [?] via the Intrinsic Pathway (?) or via the Extrinsic Pathway (?) to form [?].

factor X IXaVIlla-Ca++-PL VIla-Ill-Ca++ Prothrombinase/Xa-Va-Ca++-PPL

This [?] complex converts [?] to [?] which then cleaves [?] into [?].

prothrombinase prothrombin thrombin fibrinogen fibrin

Conversion of Fibrinogen to Fibrin STEPS: 1. [?] cleaves the a and B chains only (releasing fibrinopeptides A and B) forming soluble fibrin monomer/unstable gel. 2. [?] aggregate spontaneously end to end, side to side to form (?) thus vulnerable to enzyme plasmin (also soluble in 5M urea). 3. [?] crosslinks adjacent fibrin monomers by forming COVALENT bonds to form (?)

Thrombin Fibrin monomers; soluble fibrin polymers Factor XIII: XIlla + Ca++; stable and insoluble clot

What activates factor XIII to XIIIa?

Thrombin, Collagen

The key initiating step is the exposure of TF to the circulation and reaction of [?] with [?].

TF factor VII

The [?] complex can enzymatically activate factors [?] and [?].

TF-factor/VIla X IX

The initial activation of (?) may be important in getting the coagulation cascade started, however, (?) rapidly inactivates the (?).

factor X to Xa tissue factor pathway inhibitor (TFP) TF-VIla-Xa complex

The major action of the (?) in vivo is the activation of factor IX to IXa, which then activates factor X to Xa.

TFVIla complex

Consequently, (?) is converted to thrombin, then (?) is converted to fibrin.

prothrombin fibrinogen

Factors (?) have positive feedback activity on earlier steps of the cascade

Xa and IIa

Thrombin Feedback Mechanism

Activation of Coagulation Inhibitor to Coagulation

• It is autocatalytic or self-perpetuating

Activation of Coagulation

• Low level of thrombin activates

Activation of Coagulation V and VIII

• Activates XIlI and XI

Activation of Coagulation

• Induces platelet aggregation

Activation of Coagulation

• Controls excessive coagulation

Inhibitor to Coagulation

• Increase concentration of thrombin

Inhibitor to Coagulation

destroys V and VIII

Inhibitor to Coagulation

activates Protein C

Inhibitor to Coagulation

Protein C and S increase plasminogen activation

Inhibitor to Coagulation

Promote plasmin generation (fibrinolysis)

Inhibitor to Coagulation

: activates VIII to VIIIa

Factor II, X, residual thrombin (low level)

: activates FV

Thrombin, residual thrombin (low level)

: inhibits FV and VIII

residual thrombin (high level)

- regulatory mechanism to stop the cascade

residual thrombin (high level): inhibits FV and VIII

- continuous activation slows down the cascade

residual thrombin (high level): inhibits FV and VIII

- Thrombin is a very powerful protein that can activate many factor (FIX, FVII, FXIII)

residual thrombin (high level): inhibits FV and VIII

- to stop intrinsic pathway from accessing FX; FX will not be able to activate another thrombin/prothrombin to become thrombin

residual thrombin (high level): inhibits FV and VIII

- forms soluble fibrin to insoluble fibrin

Fibrin XIIIa

- stabilizes the clot

Fibrin XIIIa

- soluble clot only forms fibrin meshwork (does not activate)

Fibrin XIIIa