HEMATOMA NAKO ANI

• Clotting Factor I: Fibrinogen

  • Is the primary substrate of thrombin

  • Is the primary enzyme of the coagulation system

  • Is essential for platelet aggregation

  • Normal plasma conc.: 200-400 mg /dL

  • Is the most concentrated of all the plasma procoagulants

  • Is an acute phase reactant protein
• Fibrinogen Molecule

  • Is a mirror-image dimer

  • Each half consist of three nonidentical polypeptides (Aα, Bβ, y) united by disulfide bonds

  • E domain: six N-terminals assemble to form a bulky central region

  • Two D domains: three carboxyl terminals on each outer end of the molecule
• Clotting Factor II: Prothrombin

  • Activated form: Thrombin

  • Is the main enzyme of the coagulation pathway with multiple key activities.

  • Primary function: Cleave fibrinopeptides (FP) A and B from the alpha and beta chains of the fibrinogen molecule
• Thrombin: Cleaves fibrinopeptides

  • Thrombin cleaves fibrinopeptides A and B from the protruding N-termini of each of the two α and β chains of fibrinogen

  • The cleave fibrinogen is called fibrin monomer

  • The exposed fibrin monomer α and β chain ends have an immediate affinity for portions of the D domain of neighboring monomers
• 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-Thrombin Complex

  • Thrombomodulin and thrombin activates Protein C (a coagulation regulatory protein)

  • Thrombin loses its procoagulant ability to activate factors V and VIII

  • Activation of Protein C: Destroys FV and FVIII

  • Thrombin-thrombomodulin also activates TAFI
• Vitamin K-Dependent Prothrombin Group

  • Are named the prothrombin group because of their structural resemblance to prothrombin

  • All proteins under this group have 10 to 12 glutamic acid units near their amino terminal end

  • Only protein S and Z are cofactors
• Vitamin K

  • Is a quinone found in green leafy vegetables and is produced by the intestinal organisms Bacteroides fragilis and Escherichia coli

  • Catalyzes an essential posttranslational modification of the prothrombin group (glutamic acid is modified to y-carboxyglutamic acid when a second carboxyl group is added to the y carbon)
• Proteins Induced by Vitamin K Antagonists (PIVKA) factors

  • Or 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
• Clotting Factor III: Tissue Factor

  • Located on membranes of fibroblasts and smooth muscle cells • Is expressed in high levels in cells of the brain, lung, placenta, heart, kidney, and testes

  • Under normal conditions, this is not expressed on blood vessel cells

  • In injury, exposure of TF leads to the activation of coagulation through VIIa
• Clotting Factor IV: Ionized Calcium

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

  • Serine proteases bind to negatively charged phospholipid surfaces, predominantly phosphatidyl serine, through positively charged calcium ions

  • Is referred to by its name or chemical symbol (Ca2+), not by its numeral
• Clotting Factor V

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

  • Is released as partially activated factor V during platelet activation

  • Factor Va is a cofactor to Xa in the prothrombinase complex in coagulation
• Prothrombinase Complex

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

  • The initial small amount of thrombin generated activates the first V to Va
• Clotting Factor VI

  • Was assigned to a procoagulant that later was determined to be activated factor V

  • Was withdrawn from the naming system and never reassigned
• Clotting Factor VII

  • About 1%-2% is present normally in blood in

  the activated form, but it is inert until bound to

  tissue factor

  • Exposure of tissue factor during vessel injury

  activates the coagulation cascade through FVII

  • The activation of FVII is rate limited by the

  injury itself
• Coagulation

  1. Thrombin cleaves FVIII from vWF and activates FVIII

  2. FVIIIa binds to activated platelets and forms the intrinsic tenase complex with factor IXa and Ca2+
• Clotting Factor VIII

  Is produced primarily by hepatocytes but also by microvascular ECs in lung and other tissues<br>Free form is unstable in plasma (circulates bound to vWF)<br>Deteriorates more rapidly than the other coagulation factors in stored blood<br>Its production is governed by genes carried on the X chromosome<br>Is a cofactor that circulates linked to a large carrier protein, vWF<br>FVIII and vWF are key proteins for hemostasis
• Von Willebrand Factor

  • Is a large multimeric glycoprotein that participates in

  platelet adhesion

  • Transports the procoagulant factor VIII

  • Is composed of multiple subunits that are produced by

  ECs and megakaryocytes (single subunit - 240,000

  Daltons; multiple – 500,000 – 20,000,000 Daltons)
• Von Willebrand Factor

  • Are stored in alpha granules in platelets and

  in Weibel-Palade bodies in EC

  • Is an acute phase reactant protein

  • Group O individuals have lower levels of vWF

  than any other blood type
• 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
• ADAMTS-13

  • a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13

  • Degrades vWF into smaller multimers
• Clotting Factor IX: Christmas Factor

  • The production of the two plasma procoagulants,

  Factor VIII and Factor IX, are governed by genes

  carried on the X chromosome

  • Activated by the extrinsic tenase

  • Forms the intrinsic tenase complex with Factor

  VIII
• Clotting Factor X: Stuart-Prower Factor

  • Activated by the extrinsic tenase

  • Forms the prothrombinase complex together

  with Factor V
• Clotting Factor XI

  • Is activated by the contact factor complex

  • More significantly activated by thrombin

  • Activates Factor IX
• Contact Factor Complex

  • Consists of Factor XII, HMWK, and Pre-K

  • Factor XII: Hageman factor

  • HMWK: Fitzgerald factor

  • Pre-K: Fletcher factor

  • Are so named because they are activated by

  contact with negatively charged foreign surfaces
• Contact Factor Complex

  • Activates factor XI

  • Deficiencies of the factors under this

  complex do NOT cause clinical bleeding

  disorders
• 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
• Clotting Factor XIII: Fibrin-Stabilizing Factor

  • Is a heterodimer:

  =Alpha subunit is produced mostly by megakaryocytes and monocytes

  =Beta subunit is produced in the liver

  =• Activated by thrombin

  • Covalently cross-links fibrin polymers to form a

  stable insoluble fibrin clot

  • 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
• Coagulation Pathway Complexes

  1.Intrinsic tenase

  2.Extrinsic tenase

  3.Prothrombinase
• Coagulation Pathway Complexes

  • Each complex 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

  • Factor VII

  Intrinsic tenase

  • Factor IXa : Factor VIII

  Prothrombinase

  • Factor Xa : Factor Va
• Extrinsic tenase

  • Activates Factor IX and X

  Intrinsic tenase

  • Activates Factor X more efficiently

  Prothrombinase

  • Converts prothrombin to thrombin
• The Coagulation System

  • The pathways were characterized as

  cascades in that as one enzyme became

  activated, it in turn activated the next

  enzyme in sequence
• Coagulation Pathways:

  1.Intrinsic Pathway

  2.Extrinsic Pathway

  3.Common Pathway
• Intrinsic Pathway

  • The reaction system begins with factor XII and

  culminates the fibrin polymerization

  • Factor XII could be found in blood (therefore

  "intrinsic")

  • The coagulation factors in order of reaction are:

  o Factor XII, pre-K, HMWK, XI, IX, VIII, X, V, II, I

  APTT
• Extrinsic Pathway

  • Formation of TF:VIIa has since proven to be the

  primary in vivo initiation mechanism for

  coagulation

  • TF is NOT present in blood (has been called

  "extrinsic")

  • Includes the following factors:

  o Factors VII, X, V, II, I

  Prothrombin Time (PT)
• Common Pathway

  • The two pathways (intrinsic and extrinsic) have

  in common Factors X, V, II, and I
• The Hemostatic System

  Normal physiologic coagulation requires the

  presence of two cell types for formation of

  coagulation complexes:

  1.Cells that express TF (usually extravascular)

  2.Platelets (intravascular)