6: Coagulation System Part I Flashcards
Is the primary substrate of thrombin
Factor I: Fibrinogen
Is the primary enzyme of the coagulation system
Factor I: Fibrinogen
Is the most concentrated of all the plasma procoagulants
Factor I: Fibrinogen
Acute phase reactants:
- Fibrinogen
- Prothrombin
- Factor VIII
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
Is the main enzyme of the coagulation pathway with multiple key activities
Factor II: Prothrombin
Activated form of factor II
Thrombin
What is the primary function of Factor II
Cleave fibrinopeptides (FP) A and B from the alpha and beta chains of the fibrinogen molecule
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
Thrombomodulin and thrombin activates
Protein C
in Thrombomodulin-Thrombin Complex, Thrombin loses its procoagulant ability to activate factors
factors V and VIII
because Activation of Protein C: destroys FV and FVIII
Thrombin-thrombomodulin also activates
TAFI
Vitamin K-Dependent Prothrombin Group
Procoagulants:
Prothrombin II
VII
IX
X
Regulatory proteins:
Protein C
Protein S
Protein Z
(Only protein S and Z are cofactors)
Clotting factor Located on membranes of fibroblasts and smooth muscle cells
Factor III: Tissue Factor
Under normal conditions, this is not expressed on blood vessel cells
Factor III: Tissue Factor
In injury, exposure of _____ leads to the activation of coagulation through VIIa
Factor III: Tissue Factor
Is required for the coagulation complexed that assemble on platelet or cell membrane phospholipids
Factor IV: Ionized Calcium
Is a glycoprotein circulating in plasma and also present in platelet alpha granules
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
Is produced primarily by hepatocytes but also by microvascular ECs in lung and other tissues
Factor VIII: Antihemophilic Factor
Free form is unstable in plasma (circulates bound to vWF)
Factor VIII: Antihemophilic Factor
Explain what happens to FVIII during coagulation:
- 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
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
ADAMTS-13 meaning
A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
Degrades vWF into smaller multimers
ADAMTS-13
governed by genes carried on the X chromosome
Factor VIII and Factor IX
Activated by the extrinsic tenase
Factor IX: Christmas Factor
Forms the intrinsic tenase complex with Factor VIII
Factor IX: Christmas Factor
Activated by the extrinsic tenase
Factor IX: Christmas Factor
Factor X: Stuart-Prower Factor
Forms the prothrombinase complex together with Factor V
Factor X: Stuart-Prower Factor
Is activated by the contact factor complex
Factor XI: Plasma Thromboplastin Antecedent
Clotting factor more significantly activated by thrombin
Factor XI: Plasma Thromboplastin Antecedent
Clotting factor that activates Factor IX
Factor XI: Plasma Thromboplastin Antecedent
Contact Factor Complex is consists of:
Factor XII, HMWK, and Pre-K
they are activated by contact with negatively charged foreign surfaces
Contact Factor Complex
Complex that activates factor XI
Contact Factor Complex
Activation of the Contact Factor Complex:
- Factor XIIa transforms pre-K into its active form, Kallikrein
- Kallikrein cleaves HMWK to bradykinin
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
Factor XIII is a heterodimer;
Alpha subunit is produced mostly by _____________
Beta subunit is produced in the _________
Alpha - megakaryocytes and monocytes
Beta - liver
Covalently cross-links fibrin polymers to form a stable insoluble fibrin clot
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
Factor XIII: Fibrin-Stabilizing Factor
Extrinsic tenase Components:
VIIa, tissue factor, phospholipid, and Ca2+
Extrinsic tenase activates:
IX and X
Intrinsic tenase Components:
IXa, VIIIa, phospholipids, and Ca2+
Intrinsic tenase activates:
Factor X more efficiently
Prothrombinase components:
Xa, Va, phospholipids, and Ca2+
Prothrombinase converts:
prothrombin to thrombin
INTRINSIC PATHWAY
Factor XII, pre-K, HMWK, XI, IX, VIII, X, V, II, I
EXTRINSIC PATHWAY
Factors VII, III, X, V, II, I
COMMON PATHWAY
Factors X, V, II, and I
Normal physiologic coagulation requires the presence of two cell types for formation of coagulation complexes:
- Cells that express TF (usually extravascular)
- Platelets (intravascular)
Coagulation can be described as occurring in two phases:
- Initiation
- Propagation
occurs on tissue factor-expressing cells (produces 3%-5% of the total thrombin)
Initiation
occurs on platelets (produces 95% or more of the total thrombin)
Propagation
Provide a surface for formation and amplification of intrinsic tenase and prothrombinase complexes
COAT Platelets
Principal Regulators:
- TFPI
- Antithrombin
- Activated Protein C
Is a Kunitz-type serine protease inhibitor
Tissue Factor Pathway Inhibitor
Is the principal regulator of the TF pathway
Tissue Factor Pathway Inhibitor
Kunitz of TFPI:
binds to and inhibits factor Xa
Kunitz-2 domain
Kunitz of TFPI:
binds to and inhibits the VIIa:TF complex
Kunitz-1 domain
cofactor of APC and TFPI; enhances factor Xa inhibition by TFPI tenfold
Protein S
In intact normal vessels, thrombin avidly binds the EC membrane protein thrombomodulin and triggers the
Protein C Pathway
Is a transmembrane protein that binds protein C adjacent to the thrombomodulin-thrombin complex
EPCR
augments the action of thrombin-thrombomodulin at least 5-fold in activating protein C to the serine protease APC
EPCR
Cofactor that binds and stabilizes APC
Protein S:
Protein S Is synthesized in the liver and circulates in the plasma in two forms:
- Free protein S (40%),
- Bound protein S (60%)
is covalently bound to C4bBP; cannot participate in the protein C anticoagulant pathway
Bound protein S
Was the first of the coagulation regulatory proteins to be identified
Antithrombin
Is a serine protease inhibitor (serpin) that binds and neutralizes serine proteases
Antithrombin
Requires heparin for effective anticoagulant activity
Antithrombin
an inhibitor that primarily targets thrombin
Heparin cofactor II (HC II)
Is available from endothelium-associated mast cell granules or as EC heparan sulfate
Heparin
Laboratory measurement of _______ is used as an indicator of thrombin generation.
Turnaround time (TAT)
is a potent inhibitor of factor Xa
Protein Z-dependent Protease Inhibitor (ZPI)
Also inhibits Factor XIa (does not require protein Z)
Protein Z-dependent Protease Inhibitor (ZPI)
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
