HEMATLOGY 2 UIC-MLS

Clinical Hematology

Prelim Topic 4- Secondary Hemostasis

[TRANS] TOPIC 4: SECONDARY HEMOSTASIS

o b. Thrombin – fibrin
OUTLINE
1) Overview of Hemostasis Blood vessel
2) Secondary Hemostasis
3) Clotting Factors (Zymogens/ Enzyme precursors/ Inactivated
Enzymatic Factors)
A. Classification: According to Function
B. Classification: According to Physical Properties Thromboplastin ExPosure of
C. Classification: According to Coagulation Pathway collagen
D. Regulatory Proteins
4) Coagulation Cascade
A. Intrinsic Pathway
B. Extrinsic Pathway Extrinsic Intrinsic
C. Common Pathway
5) Conversion of Prothrombin to Thrombin
6) Conversion of Fibrinogen to Fibrin
7) Fibrinolysis

OVERVIEW OF HEMOSTASIS Common Pathway

 Coagulation- Sequential process by which multiple
plasma enzymes, cofactors, and other related
substances interact in sequence to form an insoluble
fibrin clot
 Fibrinolysis- Final stage of coagulation in which the
fibrin clot is digested by plasmin
SECONDARY HEMOSTASIS
 Involves the enzymatic activation of series of plasma
proteins in the coagulation system to form a fibrin
meshwork.
 Goal: formation of irreversible clot (fibrin)
 Coagulate cascade: domino effect
 Involves pathway:
o Extrinsic: upon release of thromboplastin
o Intrinsic: collagen
o Common: both
 Formation of Prothrombinase complex
o a. Prothrombin - thrombin
CLOTTING FACTORS (ZYMOGENS/ ENZYME
PRECURSORS/ INACTIVATED ENZYMATIC
FACTORS) OR PROCOAGULANT
 Actual proteins that interact during the coagulation
process
 During clotting, procoagulants are sequentially
activated, producing a localized thrombus
 Synthesized in the liver
o Except factor III and IV
 14 Clotting Factors
o CF I – XIII (there’s NO CF VI), PK, HMWK
 Circulates on its inactive form
o Except factor III and IV
 CF III: tissue factor
 CF IV: calcium factor
 Factor VIII – produced in a number of tissues
(however, major production site is liver)
 The vWF portion of VIII:vWF – made by
megakaryocytes and endothelial cells •
 Increased in liver disease are Factors I and VIII
 Zymogens: inactive form of most coagulation factors
 All coagulation factors are serine proteases, in active
form, EXCEPT factors I, III, V, VIII, High-molecular
weight kininogen, and XIII (transglutaminase)
 Nomenclature:
o Without “a”: inactivated form
o With “a”: activated form
 Classified into two: Function and Physical Properties
and also classified by their pathways
ACCORDING TO FUNCTION
SUBSTRATE
 binds to active site producing
o Clotting Factor I (Fibrinogen)
o A precursor of fibrin and when exposed to
thrombin, it will produce fibrin monomer and
aggregate to form polymerized fibrin clot.
COFACTORS
o accelerates/enhances enzymatic reactions

PADAYHAG, RIGIDOR S. | MLS-3D 1

 HEMATLOGY
Clinical Hematology UIC-MLS
2Prelim Topic 4- Secondary Hemostasis

 Table 1: PLASMA COAGULATION FACTORS

FACTOR Preferred Other Name Active Genetic Disorder Half- life Molecular Important Notes
Name form/Function (hr) Weight
(Dalton)and
Mean Plasma
I Fibrinogen Fibrin clot Congenital 100-150 340,000 If <80 mg/dL = Inc. PT
afibrinogenemia 200-400mg/dL and APTT
Familial renal
amyloidosis
II Prothrombin Prethrombin Serine Protease Prothrombin 60 71,600
G20210A 10 mg/dL
Thrombophilia
III Tissue Factor Tissue thrombo- Cofactor Insoluble 44,000
plastin None
IV Calcium Serine Protease N/A 40
8-10 mg/dL
V Proaccelerin Labile factor Cofactor Activated Protein C 24 330,000 Conc. decreases on
Accelerator resistance 1 mg/dL storage Deficiency:
globulin (aCg) Owren’s dse.; Labile
Factor dse.,
Parahemophilia

VII Proconvertin Stable factor Serine Protease Congenital factor 6 50,000 First factor to be
SPCA (Serum VII deficiency 0.05 mg/dL affected by Warfarin
Prothrombin therapy
Conversion
Accelerator)
VIII:C Antihemophilic AntihemoPhilic Cofactor Hemophilia A 12 330,000 Dec. conc. on storage;
Factor globulin 0.01 mg/dL Deficiency:
AntihemoPhilic emophilia A/ Classic
factor A Platelet Hemophilia; vWD
Cofactor 1
VWF Von Willebrand 24 600k-20M Largest molecule in
Factor 1 mg/dL human plasma
IX Plasma Christmas factor Serine Protease Hemophilia B 24 57,000 Deficiency:
Thromboplastin Antihemophilic 0.3 mg/dL Hemophilia B/
Component factor B Platelet Christmas Disease
Cofactor 2
X Stuart-Prower Stuart factor Serine Protease Congenital Factor X 48-52 58,000
Factor Prower factor deficiency 1 mg/dL
AutoProthrombin
III
XI Plasma AntihemoPhilic Serine Protease Hemophilia C 48-84 143,000 Deficiency:
Thromboplastin factor C Rosenthal 0.5 mg/dL Hemophilia C/
Antecedent Jewish Descent syndrome Rosenthal Syndrome
(common is
Ashkenazi Jews
XII Hageman Factor Glass factor Serine Protease Hereditary 48-70 84,000 NO BLEEDING
Contact factor angioedema type III 3 mg/dL TENDENCIES
XIII Fibrin- Laki-Lorand Transglutaminase Congenital Factor
Stabilizing factor XIIIa/b deficiency
Factor Fibrinase
Plasma
transglutaase
Fibrinoligase
Prekalikrein Fletcher factor Serine Protease Kininogen 35 85,000
(PK) deficiency 35-50
HMWK Fritzgerald factor Serine Protease Kininogen 156 120,000
Contact deficiency 3 mg/dL
activation
cofactor Williams
factor Flaujeac
factor

o assist in activation of zymogens  HMWK

o Clotting Factor III (Tissue factor) ENZYMES
o Labile Factors:  Serine proteases (CF II, VII, IX, X, XI and XII)
 Clotting Factor o Activated enzymatic factors
 Clotting Factor VIII
PADAYHAG, RIGIDOR S. | MLS-3D 2
 HEMATLOGY
Clinical Hematology UIC-MLS
2Prelim Topic 4- Secondary Hemostasis

o Cleaved PePtide bonds  Inhibited by oral anticoagulant (warfarin)

o Roman numeral followed by a suffix –a  NOT consumed during clotting (except II)
o Ex. IIa, VIIa, Xa, XIa  Present in fresh and stored Plasma and serum
o No biologic activity  Help CF to interact with one another
o ALL coagulation factors are serine Proteases CONTACT
upon activation EXCEPT factor XIII and  Factors XI, XII, PK, HMWK
Fibrinogen  Vit K independent; Ca2+ independent
o Activated enzymatic factors  Intrinsic coagulation Pathway
o Cleaved PePtide bonds  Moderately stable
o Roman numeral followed by a suffix –a  NOT consumed during coagulation
o Ex. IIa, VIIa, Xa, XIa  It requires negatively charge particle/substrate or
o No biologic activity foreign substance
o ALL coagulation factors are serine Proteases o In vivo: collagen and In vitro: kaolin/glass tube
upon activation EXCEPT factor XIII and ACCORDING TO COAGULATION PATHWAY
Fibrinogen  Extrinsic pathway
TRANSAMINASE o Factor III and VII
 act on the final Product of system; stabilize clot  Intrinsic pathway
o Clotting Factor XIII – ONLY o Factor VIII, IX, XI, XII
ACCORDING TO PHYSICAL PROPERTIES: o HMWK and PK
FIBRINOGEN  Common pathway
 Factors I, V, VIII, XIII o Factor I, II, V, X
 Largest group because of Factor VIII Table 2: Classification of Coagulation/Clotting Factors
 Most labile Categories of Coagulation Factors by Hemostatic Function
 Only group that acts as substrates for PLASMIN Substrate Factor I (Fibrination)
 Only group present in α granules of platelets (except
Cofactors Factor V
XIII and VIII:C)
Factor VIII
 Consumed during clotting (therefore not in serum) Enzymes Serine Protease Ia
 Thrombin-sensitive group Factor IXa
 Absent in serum Factor Xa
 Vit K independent; Ca2+ dependent Transaminase
 Increased in: “PISO” Factor XIIIa
 ↑ Acute Phase (Pregnancy and inflammation) Prekallikrein
 Factor VIII complex: Classification of Coagulation Factors by Physical Properties
o a) Factor VIII:C Contact Group Factor 11-12
 Coagulation (Procoagulant Portion) Prekallikrein
 Low MW Portion of CF VIII HMWF
 Classic Hemophilia/Hemophilia A Prothrombin Group / Vitamin K Factor 2-7-9-10
o Factor VIII:vWF Dependent Group
 Should be carried by vWF to be stable Fibrinogen Group Factor 1-5-8-13
 Platelet adhesion Group Contact Prothrombin Fibrinogen
 vWF: arise from endothelial cells or
megakaryocyte Absorbed by NO YES NO
Al3OH / BaSO4
o Factor VIIIR:Ag (Related Antigen) -
Vit. K Dependent NO YES NO
Immunologic activity
o Factor VIIIR:RCo (Related Ristocetion) Calcium NO YES YES
 Important in Platelet aggregation Dependent
 Demonstrates Ristocetin cofactor activity Consumed in NO NO except II YES
PROTHROMBIN (VITAMIN K DEPENDENT GROUP Clotting
Found in Serum BOTH BOTH PLASMA
 Factors II, VII, IX, X or Plasma (except II in S) except V/VIII
 Synthesized in the liver in the presence of Vit. K Classification of Coagulation Factors by Coagulation Pathways
 Vit K dependent; Ca2+ dependent
 Adsorbed by BaSO4 and Al(OH)3 Intrinsic 12-11-9-8/ HMWK/PK
 70% is being used up during clotting. Thrombin ( IIa) Extrinsic 3-7
is a potent platelet aggregator that also functions as Common 10-5-2-1
procoagulant, coagulation inhibitor and tissue repair.
 Vitamin K gammacarboxylation of glutamic acid
 Stable
PADAYHAG, RIGIDOR S. | MLS-3D 3
 HEMATLOGY
Clinical Hematology UIC-MLS
2
Prelim Topic 4- Secondary Hemostasis

 NOTE: Vitamin K
Dependent:
o Protein C
o Protein S
o Protein Z
 Vit.K=carboxylation of
glutamic acid intog amma
carboxyl glutamic acid.
Must have 2 carboxyl group
in order to become
functional.
 Warfarin=inhibits
epoxidereductaseto
reduceVit.K
 Extrinsic tenase
o Components: VIIa,
tissue factor,
phospholipid and
Ca2+
o Activates IX and X
 Intrinsic tenase
o Components: IXa,
VIIIa, phospholipid,
and Ca2+
o Activates X
 Prothrombinase
o Components: Xa. Va,
phospholipid and
Ca2+
o Activates prothrombin
REGULATORY PROTEINS  α2 macroglobulin: forms a complex with thrombin,
 To maintain a complex and delicate balance between kallikrein and plasmin, thus inhibiting their activities
thrombosis and abnormal bleeding PROTEIN C
o Slow the activation of procoagulants and  Activated by thrombin-thrombomodulin
suppress thrombin production  Protein S as cofactor
o Ensure coagulation is localized, not systemic o 40% - free
o Prevent excessive clotting or thrombosis o 60% - bound to C4bBP
 Major site of inhibition: endothelium and platelet  Inactivates Factor Va and VIIIa
TISSUE FACTOR PATHWAY INHIBITOR  Protein C and S: Degrades Factor Va and VIIIa
 Principal regulator of the tissue factor pathway  Extrinsic pathway inhibitor; Lipoprotein-associated
 Synthesized by ECs and expressed on platelets Coagulation Inhibitor (LACI): inhibits the VIIa-TF
 Not functional until Factor X is activated complex
 Inhibits coagulation via two steps:  C1 inhibitor: inactivator of FXIIa and Kallikrein, it also
o 1. Inactivating Xa inhibits FXIa and plasmin
o 2. TFPI:Xa complex binds to TF:VIIa COAGULATION CASCADE
 Protein S – cofactor  Coagulation cascade is composed of an extrinsic and
ANTITHROMBIN AND SERPINS intrinsic pathway, which eventually merge into
 Antithrombin – neutralizes all serine proteases, one(common pathway).
except Factor VIIa INTRINSIC PATHWAY
o Antithrombin III: major inhibitor of thrombin;  Collagen is negatively charged
o also inhibits factors Ixa, Xa, Xia, XIIa, kallikrein  Activation occurs when a vessel is injured, exposing
and plasmin the subendothelial basement membrane and
 Heparin cofactor II: inhibit thrombin collagen
 ZPI – inhibits Xa and Xia  This leads to the activation of the “Contact Factors”,
 Protein C inhibitor – inhibits APC, thrombin, Xa, XIa, Factor XII together with Factor XI, HMWF, and
and urokinase Prekallikrein.
 α1 antitrypsin: inhibitor of thrombin, Xa and Xia

PADAYHAG, RIGIDOR S. | MLS-3D 4

 HEMATLOGY
Clinical Hematology UIC-MLS
2Prelim Topic 4- Secondary Hemostasis

 The intrinsic system is more complex and present

INTRINSIC PATHWAY
XII → XIIa
(Not all are converted, only partially)
↓ Thromboplastin Antecedent PTA; F XII which in the
XIIa + HMWK + PK + Kalikrein
(HMWK serves as backup for XIIa to convert PK to K)
↓ to form a complex that activates Stuart Factor (F X).
K + HMWK → XII → XIIa
↓ 
K + XIIa→Plasminogen → Plasmin
K + XIIa converts Plasminogen to Plasmin Part of fibrinolytic
system)
↓ o Activated by the release of Factor III (TF,
XII →XIIa → XI → Xia
↓ injured tissue.
IX→ IXa
↓
IXa + FVIII:C + Ca2+ + Phospholipid (Intrinsic Tenase
Com[lex) (Phospholipid from Platelet)
↓ TT + Ca2+
Common Pathway
NOTE: ETC can also activate CF IX Passing XII and XI
[You can base the diagram above]
 INTRINSIC PATHWAY: Na-aactivate kapag mayroon foreign
body o object that will come in contact in our cells. Any nonself
ay foreign.
 It will start in Factor XII.
 Ang Factor XII (named as Contact Factor) dahil nagkacome in
contact with antigen or foreign body. When it comes to contact
with antigen, it will be converted to Factor XIIa. In the presence
of High Molecular Weight Kininogen (HMWK).
 Kapag na-activate na ang Factor XIIa, it will start to activate the
Prekallikrein (PK) into Kallikrein (K), in the presence again of
HMWK.
 Kallikrein activates HMWK.
 There is a loop for PK and XIIa. Since PK was activated by XIIa
and XIIa was activated by the help of Kallikrein because of
HMWK.
 In summary, the first coagulation factor to be activated in Intrinsic
Pathway is Factor XIIa. The substance that serves as a platform
is High Molecular Weight Kininogen (HMWK). (For Extrinsic, it is
Phospholipid.)
 Factor XIIa will activate Factor XI to Factor XIa, in the presence
again of HMWK.
 Factor XIa will activate Factor IX to IXa, kahit hindi siya complex,
it will still require calcium.
 Factor IXa will not work without the help of a cofactor. Its cofactor
is Factor VIIIa. Factor IXa will activate VIIIa and then XIa and
VIIIa complex in the presence of calcium at the phospholipid
platform, it will convert Factor X to Xa.
 In summary, the component of TENASE COMPLEX in Intrinsic,
it is Factor XIa and VIIIa. For extrinsic, the component of tenase
complex is Factor III and Factor VIIa.
 The major coagulation factor of tenase complex at Intrinsic
Pathway is Factor IXa. The cofactor is Factor VIIIa.
 The required in tenase complex in INTRINSIC pathway to convert
X to Xa is CALCIUM ONLY.
only in higher life forms. (e.g., birds and reptiles
possess only extrinsic system).
 Exposed collagen activates Hageman Factor (F XII).
Activated F XII activates plasma enzyme. Plasma
presence of Ca2+ activates Christmas Factor (F IX).
 F IX interacts with antihemophilic factor (F VIII), Ca2+
EXTRINSIC PATHWAY
When blood comes in contact with injured tissue –
tissue thromboplastin (F III) interacts with
proconvertin (F VII) and Ca2+ activating Stuart Factor
(F X).
Tissue Thromboplastin) into the plasma from
 Fastest
EXTRINSIC PATHWAY
(Tissue thromboplastin will be joined by calcium)
↓
FVIII
↓
VIIa + TF
(FVII will be activated and joined by tissue factor)
↓
ETC
(Extrinsic tenase complex: every pathway should
end with tenase complex)
↓
Activation of common pathway
[You can base the diagram above]
 Nangyayari kung nagkaroon ng damage ang blood vessel.
 Nung nasugatan ka, lalabas ang tissue factor (TF), ang
tissue factor is the coagulation factor na hindi nagsti-stay sa
blood. So, kung nasugatan ka, lalabas si TF sa blood
vessel.
 Tissue factor will look for the complementary coagulation
factor which is the Factor VII. I-aactivate ng TF si Factor VII
kaya magiging Factor VIIa.
 And then, magfoform ng Tissue Factor VIIa Complex. –
 Kapag complex ang coagulation factors, they will require a
support coagulation factor that is usually Calcium.
 Ang trabaho na nung TF-VIIa Complex is to convert Factor
X to Xa. It is also called Tenase Complex. - Ang component
ng Tenase Complex sa Extrinsic ay ang tissue factor (factor
III) at factor VII or VIIa
 The major coagulation factor of tenase complex at Extrinsic
Pathway is Factor III. The cofactor is Factor VIIa.
 The required in tenase complex in EXTRINSIC pathway to
convert X to Xa is CALCIUM AND PHOSPHOLIPID.

PADAYHAG, RIGIDOR S. | MLS-3D 5

 HEMATLOGY
Clinical Hematology UIC-MLS
2Prelim Topic 4- Secondary Hemostasis

COMMON PATHWAY ADDITIONAL NOTES

 Activated F X in the presence of Ca2+ forms  Factor IIa works to convert Factor I to Ia. Fibrinogen
complexes with accelerin (F V) to form prothrombin to Fibrin.
activator  Kung madami na ang fibrin na na-form, it will be the
o This pathway starts with the activation of Factor one to produce the Fibrin Meshwork.
X to factor Xa by either intrinsic or extrinsic  The end product of the secondary coagulation is
pathway Fibrin Meshwork.
 Kung nagdikit-dikit na ang fibrin, mangyayari ang
COMMON PATHWAY crosslink. Para mastabilize ang Fibrin Meshwork,
kailangan ang Factor XIIIa (Fibrin Stabilizing Factor).
X → Xa  REMINDERS:
↓ o Alamin kung anong mga coagulation factor ang
Xa + Va + Ca2+ + Phospholipid (Prothrombinase nasa extrinsic lang at pang-intrinsic lang.
Complex) o Alamin kung anong coagulation factor ang
nasa both pathway
↓ o Ang nag-activate ng Intrinsic Pathway ay
Prothrombinase Foreign Body.
↓ o Ang nag-activate ng Extrinsic Pathway ay
F II: Prothrombin Damaged Vessel.
↓ CONVERSION OF PROTHROMBIN TO THROMBIN
Thrombin ← FIIa  Prothrombin – inactive precursor of enzyme thrombin.
↓ o In the presence of prothrombin activator and
CFI → fibrin Ca2+ prothrombin is converted to thrombin.
 Thrombin itself increases its own rate of formation
(positive feedback mechanism).
[You can base the diagram above]
 Thrombin formation marks a critical event in the
hemostatic process
 Ang required para ma-activate ang Factor X to Xa ay ang
 Action of Thrombin
Calcium. The major coagulation factor for X to Xa is tissue o Converts fibrinogen to fibrin
factor (Factor III).
o Activates Factor XIII
 Ang Factor Xa ay iaactivate si Factor II na prothrombin to o Enhances the activity of Factor V and VIII
Factor IIa na tatawaging THROMBIN (activated
cofactor
prothrombin).
o Induces platelet aggregation
 Para mag-work si Xa kailangan niya ng cofactor na si Factor THROMBIN-MEDIATED REACTIONS IN
V. Si Factor Xa ang maga-activate kay Factor V para HEMOSTASIS
magkaroon ng Factor Va. Ang trabaho nilang dalawa ay i- PROCOAGULANT
convert si Factor II.
 Since complex ulit silang dalawa, kailangan ulit nila ng  Induces platelet activation and aggregation
calcium.  Activates cofactor VIII to VIIIa
 Hindi protease ang Factor II kaya kailangan niya ng surface  Converts Factor XIII to XIIIa
which is the PHOSPHOLIPID.  Via autocatalysis converts Prothrombin to thrombin
 Ang Xa-Va complex ay naga-activate ng Prothrombin, ang  Low level = enhance factors V and VIII
tawag sa kanila ay Prothrombinase Complex. o Negative feedback mechanism
 In summary, ang component ng Prothrombinase Complex o ↓thrombin = ↑ CF V and VIII
sa Extrinsic Pathway ay Xa at Va. Ang nagactivate kay Xa  Stimulate ADP
ay tenase complex, ang nag-activate kay Va ay si Xa. COAGULATION
 Ang major coagulation factor sa Prothrombinase Complex  Binds antithrombin to inhibit serine proteases
ay Xa, ang cofactor ay Va.  Binds to thrombomodulin to activate Protein C
 Ang kailangan para ma-convert ni Prothrombinase (inhibits Factor Va and VIIIa) and inhibit thrombin
Complex si Prothrombin to Thrombin ay Calcium at  High levels = inhibits factors V and VIII
Phospholipid Surface. o ↑ thrombin = ↓ CF V and VIII
 Yung pagko-convert ng Xa kay Factor II to IIa ay considered TISSUE REPAIR
na as COMMON PATHWAY  Induces cellular chemotaxis
 Ang extrinsic pathway lang ay hanggang doon sa naform si  Stimulates proliferation of smooth muscle and
Factor Xa. endothelial cells
 Release of PDGF (Promotes connective tissue
formation)

PADAYHAG, RIGIDOR S. | MLS-3D 6

 HEMATLOGY
Clinical Hematology UIC-MLS
2
Prelim Topic 4- Secondary Hemostasis

 Kung mayroon ng plasmin, it will act in the thrombus or

fibrin meshwork. After breaking the meshwork, FIBRIN
DEGRADATION PRODUCT will be formed.
 The end product of fibrinolysis is fibrin degradation
products. If it’s already produced, it means thrombus is
not existing.
 CLOT DISSOLUTION
o Plasmin is formed from plasminogen – enzyme
called activator (e.g., enzymes from urine, tears,
saliva, or bacterial enzyme streptokinase).
o Plasmin as an enzyme is involved in breaking
down fibrin into soluble fragments (fibrinolysis).
 Plasminogen may be produced by eosinophils. [Another
substance that activates plasminogen is Kallikrein

 It is a system whereby the temporary fibrin clot is

systematically and gradually dissolves and as the
CONVERSION OF FIBRINOGEN TO FIBRIN vessel heals in order to restore normal blood flow.
 Fibrinogen – plasma protein produced by the liver.  Systematic and accelerated hydrolysis of fibrin by
o Protein bound plasminogen
o Large more  Final stage of coagulation
o Alpha, beta, gamma  Begins a few hours after fibrin polymerization and
o Thrombin will cleave alPha and beta cross-linking
o Alpha beta: fibrinopeptides A & B PLASMINOGEN
 Fibrin monomers  Contains 5 glycosylated loops (kringles)
 Polymerize with each other  KRINGLES – enable plasminogen, along with TPA
o Weak bond (H-bond) and UPA, to bind fibrin lysine molecules during
 Unstable polymerization
 Thrombin converts fibrinogen to fibrin.  Fibrin-bound plasminogen becomes converted to
 Thrombin also activates fibrin-stabilizing factor (F ACTIVE PLASMIN when cleaved between arginine at
XIII) which in the presence of Ca2+ stabilizes the position 561 and valine at position 562 by neighboring
fibrin polymer through covalent bonding of fibrin bound TPA or UPA
monomers. PLASMIN
FIBRINOLYSIS  Digest clots by hydrolysis of arginine-related and
lysine-related peptide bonds
 After, in the primary hemostasis, nandito ang platelet plug at  Destroys fibrinogen and fibrin
dahil temporary, magkaclot ang fibrin meshwork kaya titibay  Produces FDP which increase vascular permeability
yung pagbara. Habang nandon yung fibrin meshwork, on and interfere with thrombininduced fibrin formation
going ang repair ng damaged vessel. Ang nagrerepair ay  Produces D-Dimer
ang endothelial cells mismo. Hindi nagpoproduce ng  Capable of digesting:
epithelial cells ang fibrin meshwork. Ang temporary platelet o i. Plasma fibrinogen
plug ay nagseserve as epoxy habang nagrerepair ang blood o ii. Factor V
vessel ng kaniyang membrange. o iii. Factor VIII
 After ng fibrin formation, mafoform ang thrombus, o iv. Fibronectin
maactivate naman ang Fibrinolysis.  Indirectly enhances or amplifies conversion of factor
 Fibrinolysis is the process of the dissolution of fibrin clot. XII to XIIa
Usually plasmin-mediated, sa blood, sa tissues mayroong  Enhances or amplifies conversion of PK to kallikrein,
plasminogen na inactive. Kapag nasugatan ang vessel, liberating kinins to kininogen
magrerelease ng TPA (Tissue Plasminogen Activator) na  Cleaves C3 fragment
maga-activate sa plasminogen para maging plasmin. PLASMINOGEN ACTIVATOR
 Kung hindi kailangan ng plasmin, ang magsasabi sa TPA na TISSUE PLASMINOGEN ACTIVATOR
tumigil ay ang PAI-1 (Plasminogen Activator Inhibitor). PAI1  Secreted by endothelial cells
ang magi-inhibit para hindi maconvert ang plasminogen to  Hydrolyzes fibrin-bound plasminogen and convert it
plasmin. to plasmin initiating fibrinolysis
 Circulating TPA is bound to inhibitors such as PAI-1

PADAYHAG, RIGIDOR S. | MLS-3D 7

 HEMATLOGY
Clinical Hematology UIC-MLS
2Prelim Topic 4- Secondary Hemostasis

UROKINASE PLASMINOGEN ACTIVATOR  Fibrin DP: if 2 D fragments or D dimer is formed

 Produced by urinary tract epithelial cells, monocytes,  Fibrinogen DP: if 1 D fragment is formed
and macrophages  DDAPP
 Plasma concentration: 2–4 ng/mL o 1-desamino-8-D-arginine vasopressin
 Does not bind firmly to fibrin o Release of tPA including endothelial cells
 Has a minor physiologic effect o Vasoactive drug
 Single Chain Urokinase (ScuPa)  Plasminogen (tPA, urokinase, CPA, streptokinase) →
o from vascular endothelium Plasmin → clot → FDPs → RES
o in vivo fibrinolysis DEGRADATION OF FIBRIN AND NON-CROSS-
o major activator of Plasminogen in GUT LINKED FIBRIN
 Double Chain Urokinase (TcuPa)  Plasma degrades fibrin clot during fibrinolysis and
o Activated by XIIa and Plasmin also native fibrinogen in a process called
CONTACT PHASE/INTRINSIC ACTIVATORS fibrinogenolysis.
 The earliest proteolytic activity results in the still
 Activated by XIIa and kallikrein
 Also HMWK, Plasma Proactivator clottable X fragment which is subsequently degraded
to the unclottable Y and D fragments. The Y fragment,
 Plasminogen can be Plasmin
THERAPEUTIC ACTIVATORS consisting of D plus E portions, is then itself split into
these components. Small peptides are also produced
 Streptokinase/staphylokinase at a number of the proteolytic cleavage.
PLASMINOGEN INHIBITOR
PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1)
 Principal inhibitor of plasminogen activation •
 Inactivates both TPA and UPA
 Prevents conversion of plasminogen to plasmin
ALPHA-2-ANTIPLASMIN
 Primary inhibitor of free plasmin
 Prevents plasmin’s premature and uncontrolled
digestion of fibrin
 Slows fibrinolysis by competing with plasminogen for
lysine residues and directly inactivating plasmin
THROMBIN-ACTIVATABLE FIBRINOLYSIS
INHIBITOR
 Activated by thrombin-thrombomodulin complex
 Cleaving exposed carboxy-terminal lysine residues
from fibrin
 Prevents binding of TPA and plasminogen to fibrin
and blocking plasmin formation
PROCESS OF FIBRINOLYSIS
 Plasminogen and tPA from endothelial cells in blood
vessels
 tPA will be activated by thrombin
 tPA and Plasminogen will be attracted to clot or fibrin “The struggle you’re in TODAY is developing the
 tPA and Plasminogen will combine to clot or fibrin strength you need for TOMORROW”
 Plasmin will be formed ARAL + DASAL + ASAL= FUTURE RMT
 Plasmin will be cleaved into two forming fragment X REFERENCES
which is still clottable
 Fragment X will be cleaved forming fragment D and University of the Immaculate Conception Powerpoint Presentation
fragment Y and Discussion Prepared By Sir Glenn
 Fragment D is not clottable and fragment Y is
clottable which will be cleaved into fragment D and E. Keohane, E. M., Smith, L. J., & Walenga, J. M. (2020). Rodak's
These are called dead end degradation Products hematology: Clinical principles and applications (5th ed.). St.
 Fibrinogen/fibrin degradation Products or Louis, MO: Elsevier.
fibrinogen/fibrin split Products
 X and Y: early degradation Products Stiene-Martin, E. A., Lotspeich-Steininger, C. A., &amp; Koepke, J. A.
 D and E: late or dead end degradation Products (1998). Clinical hematology: Principles, procedures,
 Reticuloendothelial system (RES) will cleave D and correlations. J.B. Lippincott Co.: Philadelphia, Pa.
E

PADAYHAG, RIGIDOR S. | MLS-3D 8