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Secondary Hemostasis: Role of Coagulation in Hemostasis
Secondary Hemostasis: Role of Coagulation in Hemostasis
Secondary Hemostasis
is defined as the formation of insoluble, cross-linked fibrin by activated coagulation
factors, specifically thrombin.
Fibrin stabilizes the primary platelet plug, particularly in larger blood vessels. where the
platelet plug is insufficient alone to stop hemorrhage.
Primary and Secondary Hemostasis
is the physical manifestation of fibrin formation which represents the end result of a series of
reactions of coagulation factors (plasma proteins) a.k.a. clotting factors, plasma factors, pro-
coagulants, coagulation proteins.
Clot
It is composed of platelet plug formed in primary hemostasis and fibrin formed in secondary
hemostasis.
Nomenclature of Procoagulants
Plasma transports at least 16 procoagulants, also called coagulation factors.
Nearly all are glycoproteins synthesized in the liver, although monocytes, ECs,
and megakaryocytes produce a few.
Eight are enzymes that circulate in an inactive form called zymogens.
Others are cofactors that bind, stabilize, and enhance the activity of their
respective enzymes.
Classification and Function of Procoagulants
The plasma procoagulants may be serine proteases or cofactors, except for factor
XIII, which is a transglutaminase
29 Serine proteases are proteolytic enzymes of the trypsin family and include the
procoagulants thrombin (factor IIa); factors VIIa, IXa, Xa, XIa, and XIIa; and pre-
K.3
Substrate
substance on which enzyme acts (ex: Fibrinogen)
Zymogen/ enzyme precursor
they are zymogens having no biologic activity until converted by enzymes to active
forms ( ex: II, VII, IX, X, XI, XII, PK)
Cofactor
component that aids in the activation of zymogen to active enzyme (ex: III, V, VIII,
HMWK)
Fibrinolysis
Fibrinolysis
Fibrinolysis, the final stage of coagulation (Figure 37-21), begins a few hours
after fibrin polymerization and cross-linking.
Two activators of fibrinolysis, TPA and UPA, are released in response to
inflammation and coagulation. Fibrinolytic proteins assemble on fibrin during
clotting.
Plasminogen, plasmin, TPA, UPA, and PAI-1 become incorporated into the fibrin
clot as they bind to lysine through their “kringle” loops, thereby concentrating and
localizing them to the fibrin clot.
Fibrinolysis is the systematic, accelerating hydrolysis of fibrin by bound plasmin.
Plasminogen
is a 92,000 Dalton plasma zymogen produced by the liver
It is a single-chain protein possessing five glycosylated loops termed kringles.
Kringles -enable plasminogen, along with activators TPA and UPA, to bind
fibrin lysine molecules during polymerization .
Plasmin
is a serine protease that systematically digests fibrin polymer by the hydrolysis of
arginine-related and lysine-related peptide bonds.
Bound plasmin digests clots and restores blood vessel patency. Its localization to
fibrin through lysine binding prevents systemic activity.
Free plasmin is capable of digesting plasma fibrinogen, factor V, factor VIII, and
fibronectin, causing a potentially fatal primary fibrinolysis.
Plasminogen Activation
Tissue Plasminogen Activator (TPA)
ECs secrete TPA, which hydrolyzes fibrin-bound plasminogen and initiates
fibrinolysis.
Urokinase Plasminogen Activator (UPA)
Urinary tract epithelial cells, monocytes, and macrophages secrete another
intrinsic plasminogen activator called urokinase plasminogen activator.
UPA has only one kringle region, does not bind firmly to fibrin, and has a
relatively minor physiologic effect.
Control of Fibrinolysis
Plasminogen Activator Inhibitor 1 (PAI-1)
PAI-1 is the principal inhibitor of plasminogen activation, inactivating both
TPA and UPA and thus preventing them from converting plasminogen to
the fibrinolytic enzyme plasmin.
a2-Antiplasmin
a2-Antiplasmin (AP) is synthesized in the liver and is the primary inhibitor
of free plasmin. AP is a serine protease inhibitor with the unique
characteristic of both N- and C-terminal extensions.
Thrombin-Activatable Fibrinolysis Inhibitor
TAFI is a plasma procarboxypeptidase synthesized in the liver that becomes
activated by the thrombin-thrombomodulin complex.
Fibrin Degradation Products and D-Dimer
Plasmin cleaves fibrin and produces a series of identifiable f ibrin fragments: X,
Y, D, E, and D-D
References:
-Keohane, E.M., Smith, L.J., Walenga, J.M.; (2016) RODAK’S HEMATOLOGY: Clinical
Principle and Applications (Fifth Edition) Elsevier (Singapore) Pte. Ltd.; Elsevier Inc.
-Nayak, R., Rai, S., Gupta, A.; (2012) Essentials in Clinical Hematology and Pathology (First
Edition) New Delhi, India; Jaypee Brothers Medical Publishers
-Steininger, C.A., Martin, E.A., Keopke, J.A.,; (1992) Clinical Hematology: Principles,
Procedures, Correlations Philadelphia, U.S.A.; J.B. Lippincott
-Nayak. R., Rai, S.; (2014) Rapid Review of Hematology (First Edition) New Delhi, India;
Jaypee Brothers Medical Publishers
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Philadelphia, U.S.A.; Lippincott William and Wilkins