Choose one or more of the following;
1. If I could memorize all of “CDs”, why can’t I
remember the blasted coagulation cascade?
2. O.K., so I figured out Factors I, II, V, VII,
VIII, IX, X, XI, and XII. So where the hell is
factor III, IV, and VI?
3. And why do they use Roman Numerals? I
can’t read my damned notes!
4. Who cares about this stuff anyway, I’m going
Hemostasis; “The processes of keeping the blood
liquid in the vasculature”
– Prevention of hemorrhage following vascular injury.
– Prevention of excessive clotting (thrombosis) in the vasculature.
– Vascular forces (vasoconstriction) and platelet plug
– The coagulation factors
Physiologic Anticoagulation processes
– Neutralize activated factors where vessels are intact.
A Series Of Perspectives On The
Original Publication Of Coagulation Cascade:
Davie, EW & Ratnoff, OD. (1964) Waterfall sequence for intrinsic blood
clotting. Science 145, 1310–1312
Clotting factors (Factor II, VII, etc.) are zymogens
(or proenzymes), which are activated to an active
enzyme by limited proteolysis.
– The enzymes in the coagulation system are serine
proteinases. (Serine, Aspartic acid, Histidine amino acids in
Cofactors of Cascade
– Factors V and VIII
The system is a “cascade”, i.e. waterfall.
– One activated molecule activates multiple at subsequent
– The product of one step is an enzyme for the next step.
Coagulation System Is Best Understood As
Series of Membrane-Bound Complexes:
(Modified from Furie B, Furie BC: The molecular basis of blood coagulation.
Cell 53:505, 1988.) in Hoffman’s Hematology Text.
Initiation of Coagulation Cascade
Primary process, in vivo, is the extrinsic pathway.
Tissue factor can be expressed by monocytes,
fibroblasts, smooth muscle, endothelial cells.
Tissue Factor is released in the vessel wall,
following exposure to endotoxin, inflammation,
Tissue Factor binds/activates Factor VII
TF:VIIa complex binds and activates Factor
IX to IXa (and to a minor degree X to Xa).
Tissue Factor (TF) Expression In The
45 kDa transmembrane glycoprotein
Expressed in blood vessels
Mackman N, The Role of Tissue
Factor and Factor VIIa in
Hemostasis. Anesth Analg
Membrane-Bound TF Initiates
Substrate: Factor IX, Factor X
Procoagulant Enzyme Complexes
– Tissue factor, VIIa, IX and X
Complex 2 (Tenase complex)
– IXa, VIIIa, and X
Complex 3 (prothrombinase complex)
– Xa, Va, and prothrombin (II)
All complexes on a negatively charged phospholipid (usually
Procoagulant Enzyme Complexes
Initiation of Intrinsic Pathway
High Molecular Weight
Minimal contribution to clotting, although it can activate
Possible role in blood pressure regulation, fibrinolysis, and
Fibrinogen Cleavage by Thrombin and
Cross-Linkage of Monomers By F XIIIa
XII, PK, HMWK
So You Think You Understand The
don’t deficiencies of “Contact
Factors” result in bleeding?
Why do different deficiencies of
“Intrinsic Pathway” factors lead to
markedly different severity of
bleeding, (or no bleeding)?
XII, PK, HMWK
Factor XI Deficiency:
Mild to no bleeding
Hemophilia A, B:
Tissue Factor:VIIa “Crosses” Arms
Of The Coagulation Cascade To
Activate Factor IX
Complex of TF;VIIa can activate Factor X, but
primary procoagulant effect is via activation of
factor IX to IXa.
How are Factors V, VIII, XI, XIII
Activation of Factors V, VIII, XI, XIII
Cross-Linked Fibrin Clot
Role of Factor XI
Factor XI is component of a positive feedback loop,
Thrombin activates Factor XI (along with V, VIII,
and XIII), which generates more thrombin.
Results in augmentation of fibrin generation.
Deficiencies not as sevee as VIII, IX, but more
clinically relevant than XII, Prekallikrein, High
Molecular Weight Kininogen.
VITAMIN K DEPENDENT
Factors II, VII, IX, X;
– proteins C & S
several glutamic acid
residues to γ-carboxyglutamic acid
Confers calcium binding and lipid
binding on these proteins.
Vitamin K Mediated
-Carboxylation of Glutamic Acid
Vitamin K-Dependent Factors
Factors II (Prothrombin), VII, IX, X
Protein C, Protein S
All are enzymes, except protein S.
-Carboxylation of Glutamic Acid allows
for binding to calcium, and complex
While both procoagulants and
anticoagulants are affected, the net effect of
vitamin K deficiency or antagonism is
Heparan Sulfate: AT III
Thrombomodulin: Protein C: Protein S
Tissue Factor Pathway Inhibitor
Deficiency first described in 1965.
– (Egeberg O. Inherited antithrombin III deficiency causing
thrombophilia. Thromb Diath Haemorrh 13:516-30, 1965)
AT III neutralizes the active enzymes in the coagulation
Antithrombin III (Antithrombin)
When heparan sulfate (on endothelial cells) or
heparin (mast cells, pharmaceutical) binds to AT
III, the AT III undergoes a conformational change
and binds to the active enzymes of the clotting
Thrombin (IIa), IXa, Xa, XIa are inhibited by
– Factor VIIa is resistant to AT III.
Protein C/Protein S System
Endothelial cell protein C receptor
Activated Protein C (With
cofactor Protein S) inactivates
Va and VIIIa, the cofactors of
– (Probable role in augmenting
EPCR localizes Protein C/Ca to
endothelial cell surface.
– May have role in sepsis.
– Activated to Plasmin (a serine proteinase)
– Plasmin proteolyzes fibrin and fibrinogen
– t-PA (Tissue-Plasminogen Activator)
• Localizes to fibrin clot
– u-PA (Urokinase-Plasminogen Activator)
• Localizes to cell membrane uPA receptor.
– Released by endothelial cells.
– PAI-1, PAI-2; Plasminogen Activator Inhibitors