Coagulation System (Part I) Flashcards by Gay Amor Tipolo Gacang

Is the primary substrate of thrombin

Clotting Factor I: Fibrinogen

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Is the most concentrated of all the plasma procoagulants

Clotting Factor I: Fibrinogen

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Describe Fibrinogen Molecule

✅ Is a mirror-image dimer
✅ consist of three nonidentical polypeptides
(Aα, Bβ, y) united by disulfide bonds

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six N-terminals assemble to form a bulky central region

E domain

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three carboxyl terminals on each outer end of the molecule

Two D domains

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Cleave fibrinopeptides (FP) A and B from the alpha and beta chains of the fibrinogen molecule.

Clotting Factor II: Prothrombin

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The cleave fibrinogen by thrombin is called

fibrin monomer

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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

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activates Protein C

Thrombomodulin-Thrombin Complex

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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

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The only cofactors of Vitamin K-Dependent Prothrombin Group

protein S and Z

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Vitamin K Is a quinone found in green leafy vegetables and is produced by the intestinal organisms

Bacteroides fragilis and Escherichia coli

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✅ 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

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In injury, exposure of TF leads to the activation of coagulation through

VIIa

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Is required for the coagulation complexes that assemble on platelet or cell membrane phospholipids

Clotting Factor IV: Ionized Calcium

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Serine proteases bind to negatively charged phospholipid surfaces, predominantly ________ through positively charged calcium ions

phosphatidyl serine,

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Is a glycoprotein circulating in plasma and also present in platelet alpha granules

Clotting Factor V: Proaccelerin

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is a cofactor to Xa in the prothrombinase complex in coagulation

Factor Va

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Accelerates thrombin generation more than
300,000-fold compared with Xa alone

Prothrombinase Complex

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Exposure of tissue factor during vessel injury activates the coagulation cascade through

Clotting Factor VII: Proconvertin

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Is a cofactor that circulates linked to a large carrier protein, vWF

Clotting Factor VIII: Antihemophilic Factor

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are key proteins for hemostasis

FVIII and vWF

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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+

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Is a large multimeric glycoprotein that participates in platelet adhesion

Von Willebrand Factor

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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:

1. For GP Ib/IX/V (platelet surface receptor – adhesion) 2. For GP IIb/IIIa (platelet surface receptor – aggregation) 3. Binds collagen 4. 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:

1. Factor XIIa transforms pre-K into its active form, Kallikrein 2. 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

1. Intrinsic tenase 2. Extrinsic tenase 3. Prothrombinase

Each Coagulation Pathway Complexes is composed of:

1. Vitamin K-dependent serine protease (IX, X, VII, II) 2. Nonenzyme cofactor (VIII, V, III) 3. Calcium and phospholipid

Extrinsic tenase

✅ FactorVII ✅ Activates Factor IX and X

Intrinsic tenase

✅ Factor IXa : Factor VIII ✅ Activates Factor X more eciently

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:

1. Activates platelets through cleavage of PAR-1 and PAR-2 2. Activates factor V released from alpha granules 3. Activates factor VIII and dissociates it from vWF 4. Activates factor XI 5. Splits fibrinogen peptides A and B

Provide a surface for formation and amplification of intrinsic tenase and prothrombinase complexes

COAT platelets

Principal Regulators

1. TFPI 2. Antithrombin 3. 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 eective anticoagulant activity

Antithrombin

What is the available form of Antithrombin

Heparin

Other Serine Protease Inhibitors

1. ZPI 2. Protein C inhibitor 3. α1-antitrypsin 4. α2-macroglobulin 5. α2-antiplasmin 6. 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)