Coagulation System (Part I) Flashcards
Is the primary substrate of thrombin
Clotting Factor I: Fibrinogen
Is the most concentrated of all the plasma procoagulants
Clotting Factor I: Fibrinogen
Describe Fibrinogen Molecule
✅ Is a mirror-image dimer
✅ consist of three nonidentical polypeptides
(Aα, Bβ, y) united by disulfide bonds
six N-terminals assemble to form a bulky central region
E domain
three carboxyl terminals on each outer end of the molecule
Two D domains
Cleave fibrinopeptides (FP) A and B from the alpha and beta chains of the fibrinogen molecule.
Clotting Factor II: Prothrombin
The cleave fibrinogen by thrombin is called
fibrin monomer
Functions of thrombin:
✅ Activates cofactors V and VIII and factor XI by a positive feedback mechanism
✅ Activates factor XIII
✅ Initiates platelet aggregation
✅ Activates the protein C pathway
activates Protein C
Thrombomodulin-Thrombin Complex
Thrombomodulin-Thrombin Complex
✅ activates Protein C
✅ Thrombin loses its procoagulant ability to activate factors V and VIII
✅ Activation of Protein C: Destroys FV and FVIII
✅ Thrombin-thrombomodulin also activates TAFI
The only cofactors of Vitamin K-Dependent Prothrombin Group
protein S and Z
Vitamin K Is a quinone found in green leafy vegetables and is produced by the intestinal organisms
Bacteroides fragilis and Escherichia coli
✅ des-y-carboxyl proteins
✅ Cannot participate in the coagulation reaction because they lack the second carboxyl group
✅ Results from Vitamin K deficiency or in the presence of Coumadin
Proteins Induced by Vitamin K Antagonists (PIVKA) factors
In injury, exposure of TF leads to the activation of coagulation through
VIIa
Is required for the coagulation complexes that assemble on platelet or cell membrane phospholipids
Clotting Factor IV: Ionized Calcium
Serine proteases bind to negatively charged phospholipid surfaces, predominantly ________ through positively charged calcium ions
phosphatidyl serine,
Is a glycoprotein circulating in plasma and also present in platelet alpha granules
Clotting Factor V: Proaccelerin
is a cofactor to Xa in the prothrombinase complex in coagulation
Factor Va
Accelerates thrombin generation more than
300,000-fold compared with Xa alone
Prothrombinase Complex
Exposure of tissue factor during vessel injury activates the coagulation cascade through
Clotting Factor VII: Proconvertin
Is a cofactor that circulates linked to a large carrier protein, vWF
Clotting Factor VIII: Antihemophilic Factor
are key proteins for hemostasis
FVIII and vWF
Describe During coagulation associated with FVIII
✅,During coagulation, thrombin cleaves FVIII from vWF and activates FVIII.
✅ FVIIIa binds to activated platelets and forms the intrinsic tenase complex with factor IXa and Ca2+
Is a large multimeric glycoprotein that participates in platelet adhesion
Von Willebrand Factor
Transports the procoagulant factor VIII
Von Willebrand Factor
Are stored in alpha granules in platelets and in Weibel-Palade bodies in EC
Von Willebrand Factor
Four sites of vWF:
- For GP Ib/IX/V
(platelet surface receptor – adhesion) - For GP IIb/IIIa
(platelet surface receptor – aggregation) - Binds collagen
- Binds factor VIII
a disintegrin and metalloprotease with a
thrombospondin type 1 motif, member 13
ADAMTS-13
Degrades vWF into smaller multimers
ADAMTS-13
Activated by the extrinsic tenase
Clotting Factor IX: Christmas Factor
Clotting Factor X: Stuart-Prower Factor
Forms the intrinsic tenase complex with Factor VIII
Clotting Factor IX: Christmas Factor
Forms the prothrombinase complex together with Factor V
Clotting Factor X: Stuart-Prower Factor
Is activated by the contact factor complex
Clotting Factor XI: Plasma Thromboplastin
Antecedent
More significantly activated by thrombin
Clotting Factor XI: Plasma Thromboplastin Antecedent
Activates Factor IX
Clotting Factor XI: Plasma Thromboplastin Antecedent
Contact Factor Complex is consists of
Factor XII, HMWK, and Pre-K
Activates factor XI
Contact Factor Complex
Are so named because they are activated by contact with negatively charged foreign surfaces
Contact Factor Complex
Clotting Factor XII: Hageman Factor
Is activated in vitro by negatively charged surfaces such as:
• Non-siliconized glass
• Kaolin
• Ellagic acid
Clotting Factor XII: Hageman Factor
Is activated in vivo by:
• Stents
• Valve prostheses
• Bacterial cell membranes
Activation of the Contact Factor Complex:
- Factor XIIa transforms pre-K into its active form, Kallikrein
- Kallikrein cleaves HMWK to bradykinin
● Activated by thrombin
● Covalently cross-links fibrin polymers to form a stable insoluble fibrin clot
Clotting Factor XIII: Fibrin-Stabilizing Factor
Is a transglutaminase that catalyzes the
formation of covalent bonds between the carboxyl terminals of y chains from adjacent D domains in the fibrin polymer
Clotting Factor XIII: Fibrin-Stabilizing Factor
Coagulation Pathway Complexes
- Intrinsic tenase
- Extrinsic tenase
- Prothrombinase
Each Coagulation Pathway Complexes is composed of:
- Vitamin K-dependent serine protease (IX, X, VII, II)
- Nonenzyme cofactor (VIII, V, III)
- Calcium and phospholipid
Extrinsic tenase
✅ FactorVII
✅ Activates Factor IX and X
Intrinsic tenase
✅ Factor IXa : Factor VIII
✅ Activates Factor X more e ciently
Prothrombinase
✅ Factor Xa : Factor Va
✅ Converts prothrombin to thrombin
Intrinsic Pathway
The coagulation factors in order of reaction are
Factor XII, pre-K, HMWK, XI, IX, VIII, X, V, II, I
Formation of TF:VIIa has since proven to be the primary in vivo initiation mechanism for coagulation
Extrinsic Pathway
Extrinsic Pathway
Includes the following factors:
Factors VII, X, V, II, I
The two pathways (intrinsic and extrinsic) have in common Factors
Factors X, V, II, and I
The low levels of thrombin generated in the initiation phase:
- Activates platelets through cleavage of PAR-1 and PAR-2
- Activates factor V released from alpha granules
- Activates factor VIII and dissociates it from vWF
- Activates factor XI
- Splits fibrinogen peptides A and B
Provide a surface for formation and amplification of intrinsic tenase and prothrombinase complexes
COAT platelets
Principal Regulators
- TFPI
- Antithrombin
- Activated Protein C
Is the principal regulator of the TF pathway
Tissue Factor Pathway Inhibitor
Deserve the Kunitz-type serine proteas Tissue Factor Pathway Inhibitor
✅ Kunitz-2 domain: binds to and inhibits factor
Xa
✅ Kunitz-1 domain: binds to and inhibits the
VIIa:TF complex
cofactor of APC and TFPI; enhances
factor Xa inhibition by TFPI tenfold
Protein S
Cofactor that binds and stabilizes APC
Protein S
Requires heparin for e ective anticoagulant activity
Antithrombin
What is the available form of Antithrombin
Heparin
Other Serine Protease Inhibitors
- ZPI
- Protein C inhibitor
- α1-antitrypsin
- α2-macroglobulin
- α2-antiplasmin
- PAI-1
In the presence of its cofactor protein Z, is a potent inhibitor of factor Xa
Protein Z-dependent Protease Inhibitor (ZPI)
Also inhibits Factor XIa. Inhibition of factor XIa is accelerated by two- fold in the presence of heparin
Protein Z-dependent Protease Inhibitor (ZPI)
A nonspecific, heparin-binding serpin that inhibits a variety of proteases (APC, thrombin, factor Xa, factor XIa, & urokinase)
Protein C Inhibitor
Activation of ________ - the primary step in coagulation because it could be found in blood.
Factor XII
occurs on tissue factor-expressing cells
Initiation
occurs on platelets
Propagation
produces 95% or more of the total thrombin generated
Propagation
produces 3% - 5% of the total thrombin generated
Initiation
revises thrombin’s function from a procoagulant enzyme to an anticoagulant
Protein C Regulatory System
first to be identified; inhibits Factor IIa, IXa, Xa, XIa, XIIa, PK, Plasmin
Antithrombin
inactivates thrombin
Heparin cofactor II
dependent protease inhibitor - potent inhibitor of Factor Xa; also inhibits Factor XIa
Protein Z-
inhibits APC, IIa, Xa, XIa, urokinase
Protein C inhibitor
Mixing studies or Substitution studies
Fresh Plasma
All factors are present
Mixing studies or Substitution studies
Fresh Serum
Lacks Factors I, V, VIII, XIII (Fibrinogen group)
Mixing studies or Substitution studies
Aged Plasma
Lacks Factors V and VIII (labile factors)
Mixing studies or Substitution studies
Aged Serum
Lacks Factors I, II, V, VIII, XIII (Fibrinogen group and II)
Mixing studies or Substitution studies
Adsorbed Plasma
Lacks Factors II, VII, IX, X (Vit. K-dependent group)