1.

04 FIBRINOLYSIS
Professor Kerfelcel Retoriano HEMATOLOGY 2
A.Y 2022-2023

OUTLINE
• Fibrinolysis/ Fibrinolytic System A. Disorders of Primary
A. Kinin System Fibrinolysis
• Control of Hemostasis B. Disorders of Secondary
• Plasminogen Activators Fibrinolysis
• Therapeutic Plasminogen Activators • Tests for Fibrinolysis
• Inhibitors of Fibrinolysis • Difference of Primary & Secondary
• D-dimer Test Fibrinolysis
• Disorders of Fibrinolysis • Summary

FIBRINOLYSIS/ FIBRINOLYTIC SYSTEM

• Digestion of fibrin clot
• Keeps the vascular system free of deposited fibrin/fibrin clot
• Begins with activation of plasminogen to plasmin.
• Fibrinolysis – it is the physiological process that removes insoluble fibrin clots
through enzymatic digestion of cross-linked fibrin polymers.
o Controlled by the plasminogen activator system
• Plasmin – responsible for the lysis of fibrin into fibrin degradation products.
• Fibrinogen – a three polypeptide chain that forms fibrin monomers and fibrin
polymers when degraded.
• Plasminogen – a zymogen which is normally present n the plasma and
synthesized by the liver.

Kinin System
• Involve in the activation of CONTACT PATHWAY.
o Contact pathway – consists of prekallikrein, HMWK and factor XII. This
pathway has important anticoagulant, profibrinolytic and proinflammatory roles
and has minimal influence on the coagulation cascade.
• Activated by coagulation factor XII.
• Kininogens – are proteins that are defined by their role as precursors for kinin,
but that also can have additional roles.

2 Main Types Description

High-molecular-weight kininogen Produced by the liver together with pre kallikrein. It acts
mainly as a cofactor on coagulation ad inflammation.
Low-molecular-weight-kininogen Produced locally by numerous tissues.

• Other functions of Bradykinin

o An important vascular mediator, causing vasodilation, increased vascular
permeability, and vascular smooth muscle growth and proliferation.
o Serves to stimulate vessel repair.

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CONTROL OF HEMOSTASIS
• Thrombin binding to thrombomodulin on endothelial cells activates anticoagulant
proteins C and S.
• Protein C and S inhibits activation of factor V and VIII which limits thrombin
generation.
• Tissue factor pathway inhibitor – a lipoprotein-associated molecule, inhibits
binding of tissue factor to factor VIIa.
• Antithrombin (AT) – a small protein molecule that inactivates several enzymes of
the coagulation system. A nonvitamin K-dependent protease that inhibits
coagulation by lysing thrombin and factor Xa.

PLASMINOGEN ACTIVATORS
• In blood
Intrinsic Activators
• Factor XIIa, kallikrein (binds to HMWK), HMWK
Tissue type Plasminogen Activators Urokinase – like PA
• Streptokinase
• Urokinase
Therapeutic PA
• Tissue-like Pa-manufactured in vitro by
recombinant DNA techniques
Tissue plasminogen activator (tPA) • Principal plasminogen activator
Single chain urokinase plasminogen activator (ScuPA)
Two-chain urokinase plasminogen (TcuPA)

THERAPEUTIC PLASMINOGEN ACTIVATORS

• A protease present in the urine and produced by the kidney
• Advantage over streptokinase – it lacks antigenicity
Urokinase
o Antigenic – has the ability to produce antibodies and can
react with it or induce immune response
Epsilon-aminocaproic • Useful in the treatment of primary fibrinolysis
acid (EACA) • Because it stops the activation of plasminogen to plasmin

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INHIBITORS OF FIBRINOLYSIS
α2-antiplasmin Major inhibitor of fibrinolysis
α2-macroglobulin Inhibits plasmin and kallikrein
Thrombospondin
Plasminogen Inhibitors 1 and 2
α1-antitrypsin Inhibits plasmin
Antithrombin (antithrombin III) Inhibits plasmin and kallikrein
C1-inactivator Inhibits plasmin

D-DIMER TEST
• Most specific test for DIC
• Thrombin activates fibrinolytic system with the production of plasmin at the site of
the clot.
• Plasmin lyses the fibrin and produces FDP that contain the portion called D-dimer.
• Plasmin will also lyse fibrinogen but will NOT produce the D-dimer.
• Presence of D-dimer indicates that a stable fibrin clot has been lysed.
• Found in:
o Pulmonary embolism o Arterial thromboembolism
o Deep vein thrombosis o Sickle cell disease
o DIC
FDP D-dimer
Pathological fibrinolysis + –
DIC + +

DISORDERS OF FIBRINOLYSIS
Disorder of Primary Fibrinolysis
• Excessive amount of plasminogen activators released from malignant or damaged
cells
• Converts plasminogen to plasmin in the absence of fibrin formation
• Example: Prostatic Carcinoma
• NO fibrin monomer, fibrin polymer and D-dimer

Disorders of Secondary Fibrinolysis

• Seen in DIC → inappropriate formation of fibrin within the blood vessels
• Also seen in: infections, neoplasms, snake bite and HTR
• WITH fibrin monomer, fibrin polymer, D-dimer

TESTS FOR FIBRINOLYSIS

Tests Descriptions
Whole blood Clot lysis • Normal: NO clot lysis within 48 hours
Time • Increased fibrinolysis: clot lysis <48 hours
Euglobulin Clot lysis Time • Euglobulin – portion of plasma which consist of
plasminogen, plasminogen activators and fibrinogen
• Procedure: acetic acid → precipitate euglobulin

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• Euglobulin dissolved in buffer + thrombin → clot euglobulin

Protamine Sulfate Test
Ethanol Gelation Test
Latex Agglutination Test
for D-dimer
• Normal: NO clot lysis after 2 hours
• Increased fibrinolysis: clot lysis in less than 2 hours
• Determines fibrin monomers (secondary fibrinolysis)
• Plasma + protamine sulfate → gel-like clot
• Determines fibrin monomers (secondary fibrinolysis)
• Plasma + NaOH + EtOH → (+) precipitation
• Mot specific for DIC
• Coat on the latex → anti-D-dimer antibodies
• (+) result: turbidity
o Measured through turbidimeter or nephelometric
means
• Most methods detects at least 10ng/mL of D-dimer

DIFFERENCE OF PRIMARY AND SECONDARY FIBRINOLYSIS

Test Primary Fibrinolysis Secondary Fibrinolysis
WBCLT <48 hours <48 hours
Euglobulin Clot Lysis <2 hours <2 hours
Protamine Sulfate - +
EtOH Gelation - +
D-dimer - +
 What is the most specific test for DIC? – D-dimer Test
 What is the more sensitive test for fibrin monomers? – Protamine sulfate &
Ethanol gelation
SUMMARY
BT APTT PT
Primary hemostasis ↑ N N
Intrinsic Pathway N ↑ N
(12, 11, 9, 8)
Extrinsic Pathway N N ↑
(7, 3)
Common Pathway (1, N ↑ ↑
2, 5, 10, 13)
Factor X deficiency N ↑ ↑
Factor I deficiency N ↑ ↑
**Bleeding time (BT) – represents primary hemostasis
**APTT & PT – represents secondary hemostasis
**Stypven Time – test used to measure factor X deficiency
**Thrombin Time – test used to measure factor I deficiency

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Bleeding Platelet Platelet

APTT PT Notes
Time Count function
-Dengue
↓PC ↑ ↓ N N N
-ITP
Bernard- Abnormal
↑ ↓ N N ↓GP1b
Soulier adhesion
-↓GPIIb-IIIa
Abnormal
Glanzmann ↑ N N N -↑ clot
aggregation
retraction time
-Carrier
molecule of
Abnormal
vWF ↑ N ↑ N FVIII
adhesion
-Remedy:
Cryoprecipitate
Vit. C
Scurvy ↑ N N N N
deficiency
Abnormal ↓aggregating
Granule
↑ N/↓ release of N N signals of ADP
deficiency
granules & TXA2
Hemophilia
↑ N N ↑ N
(A, B, C)
Parahemophilia
N N N ↑ ↑
(Factor V)
(+) D-dimer
(+) histiocytes
N/
DIC ↑ ↓ ↑ ↑ Remedy:
Abnormal
-Plt. Con, FFP,
Cryoprecipitate

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