Nomenclature And Intro To Coag Cascade Flashcards
Complex molecule in the plasma
VIlI/vWF
: coagulation
VIII: C
: platelet adhesion
VIII:vWF
Produced as a big complex
VIlI/vWF
Platelet adhesion
VIlI:vWF
tested by BT
VIlI:vWF
acts as an adhesive to the endothelium
VIlI:vWF
can be tested by bleeding time when deficient
VIlI:vWF
prolonged bleeding time may be caused by VWF due to defect in plt adhesion
VIlI:vWF
Starts to separate when matures in the endothelium ([?] moves to the circulation; [?] remains in the endothelium)
FVIII
VWF
cofactor (FIX+Ca)
tested by PTT
VIII:C
VIII:C APTT:
Intrinsic
VIII:C PT:
extrinsic
individual factor
VIII:C
seen in the coagulation cascade
VIII:C
“C” for
cofactor or coagulant portion of factor VIII
Serves as a cofactor to Factor IX and Calcium (needed to activate FX in the common pathway)
VIII:C
- part of “intrinsic prothrombinase”
VIII:C
Antigenic property of VIII:C
VIIIC:Ag
Tested by monoclonal antibody (antisera)
VIIIC:Ag
FVIII may have an inhibitor and attacks FVIII
VIIIC:Ag
Antigenic property of vWF
VIIIR:Ag
tested by Laurell rocket
VIIIR:Ag
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:
- Inflammation
- Pregnancy
- 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:
- Oral anticoagulants (function)
- GIT absorption problems
CONTACT GROUP
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
FV
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
FX
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
- Morawitz/Classical Theory (1905)
- Howell’s theory (1910)
- 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:
- thrombin formation
- 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
- Contact Phase
- Activation of Factor X
- Conversion of Prothrombin to Thrombin
- Formation of fibrin
- Starts with the activation XII, then activation of prekallikrein and factor XI.
- Contact Phase
via Intrinsic Pathway or via Extrinsic Pathway
- Activation of Factor X
THE COAGULATION CASCADE
- INTRINSIC System
- EXTRINSIC System / TISSUE FACTOR Pathway
- 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
- INTRINSIC System
• Sequence of reactions: - Factor [?] is activated by the foreign material into [?]
- [?] reacts weakly with [?], thus converting them into their forms
- [?] in the presence of Ca++ activates [?]
- [?] 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
