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HEMOSTASIS AND FIBRINOLYSIS

We have already noted that two essential requirements of the circulatory system are that the blood must bea liquid and that it cannot leak through the walls of the blood vessels. Meeting these two requirements is the

job of the fibrinolytic and hemostatic machinery.

Hemostasis (from the Greek hemos [blood] + stasis [standing]), or the prevention of hemorrhage, can beachieved by four methods: (1) vasoconstriction, (2) increased tissue pressure, (3) the formation of a platelet

plug in the case of capillary bleeding, and (4) coagulation or clot formation.

Vasoconstriction contributes to hemostasis because it raises the critical closing pressure - as we discusson page 455 - and thus collapses vessels that have an intravascu-lar pressure below the critical closingpressure. Vessel constriction is also promoted by chemical byproducts of platelet-plug formation and ofcoagulation. For example, activated platelets release the vasoconstrictors thromboxane A2 (TXA2) (p. 106)

and serotonin (5-HT) (p. 305). Moreover, thrombin, a major product of the clotting machinery, triggers theendothelium to generate endothelin-1 (ET-1) (p. 480), the most powerful physiological vasocon-strictor.

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Increased tissue pressure contributes to hemostasis because it decreases transmural pressure (p. 428),which is the difference between intravascular pressure and tissue pressure. Transmural pressure is the

main determinant of blood-vessel radius. Given the fourth-power relationship between flow andblood-vessel radius (p. 429), an increase in tissue pressure that causes radius to decrease by a factor of 2would diminish flow by a factor of 16. We all take advantage of this principle when we press a finger againsta small cut to stop the bleeding. A tourniquet increases extravascular pressure and can thus halt an arterialhemorrhage in a limb. Finally, surgeons routinely make use of this principle when applying hemostaticclamps to close off "bleeders."

In this section, we discuss the third and fourth methods of hemostasis, platelet-plug formation andcoagulation.

Platelets Can Plug Holes in Small Vessels

Platelets form in the bone marrow by budding off from large cells called megakaryocytes, each of which

can produce up to a few thousand platelets. In their unactivated state, these nucleus-free fragments aredisk shaped and 2 to 3 m in diameter. Normal blood contains 150,000 to 450,000 platelets per microliter.The lifespan of these platelets is about ten days.

In a highly controlled fashion, platelets plug small breaches in the vascular endothelium. Plug formation is aprocess that includes adhesion, activation, and aggregation.

ADHESION.

Normally platelets do not adhere to themselves, to other blood cells, or to endothelial membranes. Onepreventive factor may be the negative surface charge on both platelets and endothelial cells. In the case ofendothelial cells, the negative surface charge reflects the presence of proteoglycans, mainly heparansulfate. Platelet adhesion occurs in response to an increase in the shearing force (p. 429) at the surface of

platelets or endothelial cells and in response to vessel injury or humoral signals.

Platelet adhesion - the binding of platelets to themselves or to other components - is mediated by "platelet

receptors," which are glycoproteins in the platelet membrane. These platelet receptors are integralmembrane proteins belonging to a class of matrix receptors known as integrins (p. 19). They are usuallyheterodimers linked by disulfide bonds. One ligand naturally present in the blood plasma is von Willebrandfactor(vWf), a glyco-protein made by endothelial cells and megakaryocytes (and carried by the product ofmegakaryoctyes - platelets). High shear, certain cytokines, and hypoxia all trigger the release of vWf fromendothelial cells. vWf binds to the platelet receptor known as glycoprotein Ib/Ia (Gp Ib/Ia), which is a dimerof Gp Ib linked to Gp Ia.

A breach of the endothelium exposes platelet receptors to ligands that are components of the

subendothelial matrix. These ligands include collagen, which binds to Gp Ia/IIa, and fibronectin andlaminin (p. 19), both of which bind to Gp Ic/IIa.

ACTIVATION.

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The binding of the above ligands - or of certain other agents (e.g., thrombin) that we will discuss later -triggers a conformational change in the platelet receptors that initiates an intracellular signaling cascadethat leads to an exocytotic event known as the "release reaction" or platelet activation. The signal

transduction cascade involves the activation of phospholipase C (p. 100) and an influx of Ca 2+. Activated

platelets exocytose the contents of theirdense storage granules, which include ADP, serotonin, and Ca2+

.

Activated platelets also exocytose the contents of their granules, which contain several proteins,including a host of growth factors and three hemostatic factors: von Willebrand factor (see above) and two

clotting factors that we will discuss below, clotting factor V and fibrinogen. Activated platelets also usecyclooxygenase (p. 104) to initiate the breakdown of arachidonic acid to thromboxane A2, which they

release. Platelet activation is also associated with marked cytoskeletal and morphological changes as theplatelet extends first a broad lamellipodium and then many finger-like filopodia.

AGGREGATION.

Signaling molecules released by activated platelets amplify the platelet-activation response. ADP (whichbinds to P2Y12 receptors on platelets), serotonin, and TXA2 all activate additional platelets, and this

recruitment promotes platelet aggregation. Aspirin, an inhibitor of cyclooxygenase, inhibits clotting byreducing the release of TXA2. As noted above, the von Willebrand factor released by activated platelets

binds to the platelet receptor Gp Ib/Ia, thereby activating even more platelets and forming molecular bridgesbetween platelets. Platelet activation also induces a conformational change in Gp IIb/IIIa, another plateletreceptor, endowing it with the capacity to bind fibrinogen. Thus, as a result of the conformational change inGp IIb/IIIa, the fibrinogen that is always present in blood forms bridges between platelets and thusparticipates in the formation of a platelet plug. As we will see later, when cleaved by thrombin, fibrino-genalso plays a critical role in clotting.

A Controlled Cascade of Proteolysis Creates a Blood Clot

A blood clot is a semisolid mass composed of both platelets, fibrin, and - entrapped in the mesh of fibrin

-erythrocytes, leukocytes, and serum. A thrombus is also a blood clot, but the term is usually reserved foran intra-vascularclot. Thus, the blood clot formed at the site of a skin wound would usually not be called a

thrombus. The relative composition of thrombi varies with the site ofthrombosis (i.e., thrombus formation).A higher proportion of platelets is present in clots of the arterial circulation, whereas a higher proportion of

fibrin is present in clots of the venous circulation.

Platelet-plug formation and blood clotting are related but distinct events that may occur in parallel or in theabsence of the other. As we will see later, activated platelets can release small amounts of some of the

factors (e.g., Ca2+) that play a role in blood clotting. Conversely, as we have already noted, some clottingfactors (e.g., thrombin and fibrinogen) play a role in platelet-plug formation. Thus, molecular crosstalkbetween the machinery involved in platelet-plug formation and clot formation helps coordinate hemostasis.

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The cardiovascular system normally maintains a precarious balance between two pathological states. Onthe one hand, inadequate clotting would lead to the leakage of blood from the vascular system and,ultimately, to hypo-volemia. On the other hand, overactive clotting would lead to thrombosis and, ultimately,

to cessation of blood flow. The cardiovascular system achieves this balance between an antithrombotic

(anticoagulant) and a prothrom-botic (procoagulant) state by a variety of components of the vascular walland blood. Promoting an "antithrombotic" state is a normal layer of endothelial cells, which line all luminalsurfaces of the vascular system. Promoting a "pro-thrombotic" state are events associated with vasculardamage: (1) the failure of endothelial cells to produce the proper antithrombotic factors or (2) the physicalremoval or injury of endothelial cells, which permits the blood to come into contact with thrombogenicfactors that lie beneath the endothelium. Also promoting a "prothrombotic" state is the activation of plateletsby any of the ligands that bind to platelet receptors, as discussed earlier. For instance, as platelets flowpast artificial mechanical heart valves, the shearing forces can activate the platelets.

Table 17-1. PROCOAGULANT AND ANTICOAGULANT FACTORS

NAME ALTERNATE NAMES PROPERTIESProcoagulant Factors

Factor I Fibrinogen A plasma globulin

Factor Ia Fibrin

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Factor II Prothrombin A plasma 2 globulin

Synthesis in liver requires Vitamin K*

Factor IIa Thrombin A serine protease

Factor III (cofactor) Tissue factorTissue thromboplastin

An integral membrane glycoprotein;member of Type II cytokine receptor familyReceptor for Factor VIIaMust be present in a phospholipid

membrane for procoagulant activityFactor IV Ca

2+

Factor V Labile factor Proaccelerin

Accelerator globulin

A plasma protein synthesized by liver andstored in plateletsSingle-chain protein

Factor Va (cofactor) Heterodimer held together by a single

Ca2+

ionHighly homologous to Factor VIIIa

Factor VII Stable factor Serum prothrombin

conversion accelerator(SPCA)Proconvertin

A plasma proteinSynthesis in liver requires Vitamin K*

Factor VIIa A serine protease

Factor VIII Antihemophilic factor (AHF)Factor VIII procoagulantcomponent (FVIII:C)

A plasma protein with phospholipid bindingdomain

Factor VIIIa(cofactor)

Highly homologous to Factor Va

Factor IX Christmas factor Plasma thromboplastin

component (PTC)

A plasma proteinSynthesis in liver requires Vitamin K*

Factor IXa A proteaseA disulfide-linked heterodimer

Factor X Stuart factor A plasma glycoproteinSynthesis in liver requires Vitamin K*

Factor Xa A protease

Factor XI Plasma thromboplastinantecedent (PTA)

A plasma protein produced bymegakaryocytes and stored in platelets

Factor XIa A proteaseA disulfide-linked homodimer

Factor XII Hageman factor (HAF) A plasma glycoproteinFactor XIIa A protease

Factor XIII Fibrin stabilizing factor (FSF) A plasma protein stored in platelets

Factor XIIIa A transglutaminaseA tetramer of two A chains and two Bchains

HMWK High molecular weightkininogenFitzgerald factor

A plasma protein stored in plateletsKallikrein clips bradykinin from HMWK

Plasma prekallikrein Fletcher factor

Plasma kallikrein precursor

A plasma protein

Plasma kallikrein A serine proteaseKallikrein clips bradykinin from HMWK

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von Willebrandfactor

vWf A plasma glycoprotein made byendothelial cells and mega-karyocytesStabilizes Factor VIIIaPromotes platelet adhesion andaggregation

Anticoagulant Factors

TFPI Tissue factor pathway

inhibitor

Protease inhibitor produced by endothelial

cellsGPI-linked to the cell membrane

Antithrombin III AT III A plasma proteinSerine protease inhibitor, member ofserpin familyInhibits Factor Xa and thrombin, andprobably also Factors XIIa, XIa, and IXaHeparan and heparin enhance theinhibitory action

Thrombomodulin(cofactor)

Glycosaminoglycan on surface ofendothelial cellBinds thrombin and promotes activation ofprotein C

Protein C Anticoagulant protein CAutoprothrombin IIA

A plasma proteinSynthesis in liver requires Vitamin K*

Protein Ca A serine proteaseDisulfide-linked heterodimer

Protein S (cofactor) A plasma proteinSynthesis in liver requires Vitamin K*Cofactor for protein C

*See page 1226 for a discussion of vitamin K.

According to the classical view, two distinct sequences can precipitate coagulation: the intrinsic pathwayand the extrinsic pathway. It is the intrinsic pathway that becomes activated when blood comes intocontact with a negatively charged surface - in the laboratory we can mimic this process by putting blood intoa glass test tube. The extrinsic pathway is activated when blood comes in contact with material fromdamaged cell membranes. In both cases, the precipitating event triggers a chain reaction that convertsprecursors into activated factors, which in turn catalyze the conversion of other precursors into otheractivated factors, and so on. Most of these "precursors" are zymogens that give rise to "activated factors"that are serine proteases. Thus, controlled proteolysis plays a central role in amplifying the clotting signals.However, the cascades do not occur in the fluid phase of the blood, where the concentration of each ofthese factors is low. In the case of the intrinsic pathway, the chain reaction occurs mainly at the membraneof activated platelets. In the case of the extrinsic pathway, the reactions occur mainly at a "tissue factor"

that is membrane bound. Both pathways converge on a common pathway that culminates in generating

thrombin and, ultimately, "stable" fi-brin. Table 17-1 summarizes the names, synonyms, and properties ofthe procoagulant and anticoagulant factors in various parts of the clotting scheme.

INTRINSIC PATHWAY (SURFACE CONTACT-ACTIVATION).

The left branch of Figure 17-23 shows the intrinsic pathway, a cascade of protease reactions initiated byfactors that are all present within blood. When in contact with a negatively charged surface such as glass orthe membrane of an activated platelet, a plasma protein called Factor XII (Hageman factor) can becomeFactor XIIa -the suffix "a" indicates that this is the activatedform of Factor XII. A molecule called high

molecular weight kininogen (HMWK), a product of platelets that may in fact be attached to the plateletmembrane, helps to anchor Factor XII to the charged surface, and thus serves as a cofactor. However, thisHMWK-assisted conversion of Factor XII to Factor XIIa is limited in speed. Once a small amount of FactorXIIa accumulates, this protease converts prekallikrein to kallikrein, with HMWK as an anchor. In turn, the

newly produced kallikrein accelerates the conversion of Factor XII to Factor XIIa-an example of positivefeedback. On page 555, we see another example of an interaction between kallikreins and kininogens (e.g.,HMWK), in which the proteolytic activity of kallikreins on kininogens leads to the release of smallvasodilatory peptides called kinins.

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page 446D

Figure 17-23 The coagulation cascade, showing only the procoagulant factors. The abbreviations are listed in Table 17-1.

In addition to amplifying its own generation by forming kallikrein, Factor XIIa (together with HMWK) alsoproteolytically cleaves Factor XI to Factor XIa. In turn, Factor XIa (also bound to the charged surface byHMWK) proteolytically cleaves Factor IX (Christmas factor) to Factor IXa, which is a protease. Factor IXaand two downstream products of the cascade-Factors Xa and, most importantly, thrombin-proteolyticallycleave Factor VIII to Factor VIIIa, a cofactor in the next reaction. Finally, Factors IXa and VIIIa, together

with Ca2+

(which may come largely from activated platelets) and negatively charged phospholipids form a

trimolecular complex called "tenase." Tenase then converts Factor X (Stuart factor) to Factor Xa, yetanother protease.

EXTRINSIC PATHWAY (TISSUE FACTOR ACTIVATION).

The right branch of Figure 17-23 shows the extrinsic pathway, a cascade of protease reactions initiated byfactors that are outside the vascular system. Nonvascu-lar cells constitutively express an integral

membrane protein called tissue factor(tissue thromboplastin, or Factor III), which is a receptor for aplasma protein called Factor VII. When an injury to the endothelium allows Factor VII to come into contactwith tissue factor, the tissue factor nonproteolytically activates Factor VII to Factor VIIa. Subsequently,

tissue factor, Factor VIIa, and Ca2+

form a trimolecular complex analogous to tenase. Like tenase, the

trimolecular complex of [tissue factor + Factor VIIa + Ca2+

] proteolytically cleaves the proenzyme Factor Xto Factor Xa. An interesting feature is that when Factor X binds to the trimolecular complex, Factor VIIaundergoes a conformational change that prevents it from dissociating from tissue factor.

Regardless of whether Factor Xa arises by the intrinsic or extrinsic pathway, the cascade proceeds along

the "common pathway."

COMMON PATHWAY.page 446E

Figure 17-24 An abbreviated version of the coagulation cascade, showing the anticoagulant factors. The anticoagulant pathways are indicatedin red. The abbreviations are listed in Table 17-1.

Factor Xa from either the intrinsic or extrinsic pathway is the first protease of the common pathway (centerof Figure 17-23). Reminiscent of the conversion of Factor VIII to the cofactor VIIIa in the intrinsic pathway,the downstream product thrombin clips Factor V to form the cofactor Va. Factor V is highly homologous toFactor VIII, and in both cases the proteo-lytic activation clips a single protein into two peptides that remain

attached to one another. Factors Xa and Va, together with Ca2+

and phospholipids, form yet anothertrimolecular complex called prothrombinase. Prothrombi-nase acts on a plasma protein called prothrombinto form thrombin.

Thrombin is the central protease of the coagulation cascade, responsible for three major kinds of actions:

Activation of downstream components in the clotting cascade. The main action of thrombin is tocatalyze the proteolysis of a soluble plasma protein called fibrinogen (p. 432) to form fibrin

monomers that are still soluble. Fibrin monomers then polymerize to form a geloffibrin polymersthat traps blood cells. Thrombin also activates Factor XIII to Factor XIIIa, which mediates the

covalent crosslinking of the fibrin polymers to form a mesh called stable fibrin that is even lesssoluble than fibrin polymers.

1.

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Positive feedback at several upstream levels of the cascade. Thrombin can catalyze theformation of new thrombin from prothrombin and can also catalyze the formation of the co-factors Vaand VIIIa.

2.

Paracrine actions that influence hemostasis. First, thrombin causes endothelial cells to releaseNO, PGI2, ADP, von Willebrand factor, and tissue plasminogen activator (see below). Second,

thrombin can activate platelets through PAR-1, a protease-activated receptor that belongs to thefamily of G-protein - coupled receptors (p. 92). Thus, thrombin is a key part of the molecular crosstalkintroduced earlier between platelet activation and blood clotting, both of which are required foroptimal clot formation. On the one hand, thrombin is a strong catalyst for platelet activation, and onthe other hand, activated platelets offer the optimal surface for the intrinsic pathway leading toadditional thrombin generation.

3.

COAGULATION AS A CONNECTED DIAGRAM.page 446F

The concept of independent intrinsic and extrinsic branches converging on a common pathway is becomingobsolete. In such a "branching tree" (see p. 574), multiple branches converge to form larger downstreambranches, eventually converging on a single "trunk" - with no crosstalk between branches. However,coagulation is best conceptualized as a "connected diagram" (p. 574) in which the branches mayinterconnect in both the upstream and downstream directions. One example of interconnections isthrombin's multiple actions just discussed. Another example is the trimolecular complex of [tissue factor +

Factor VIIa + Ca2+

] of the extrinsic pathway, which activates Factors IX and XI of the intrinsic pathway. Inthe other direction, Factors IXa and Xa of the intrinsic pathway can activate Factor VII of the extrinsicpathway. Thus, the intrinsic pathway and extrinsic pathway are strongly interconnected to form a network.

What parts of this network are most important for coagulation in vivo? Clinical evidence suggests thatcoagulation depends largely on the extrinsic pathway. Although tissue factor is normally absent fromintravascular cells, inflammation can trigger peripheral blood monocytes and endothelial cells to expresstissue factor, increasing the risk of coagulation. Indeed, during sepsis, the tissue factor produced bycirculating monocytes initiates intravascular thrombosis.

Anticoagulants Keep the Clotting Network in Check

Thus far, our discussion has focused on the coagulation cascade and attendant positive feedback. Just asimportant are the mechanisms that prevent hemostasis from running out of control. Endothelial cells are themain sources of the agents that help maintain normal blood fluidity. These agents are of two general types,paracrine factors and anticoagulant factors.

PARACRINE FACTORS.

Endothelial cells generate prostacyclin (PGI2 ; see p. 106), which promotes vasodilation (p. 479) and thus

blood flow, and also inhibits platelet activation and thus clotting. Stimulated by thrombin, endothelial cellsalso produce nitric oxide (NO; see p. 110). Via cGMP, NO inhibits platelet adhesion and aggregation.

ANTICOAGULANT FACTORS.

As summarized in Figure 17-24, endothelial cells also generate anticoagulant factors that interfere with theclotting cascade that generates fibrin. Table 17-1 lists these factors:

Tissue factor pathway inhibitor (TFPI). TFPI is a plasma protein that binds to the tri-molecular

complex [tissue factor + Factor VIIa + Ca2+

] in the extrinsic pathway and blocks the protease activityof Factor VIIa. TFPI is GPI linked (p. 34) to the endothelial cell membrane, where it maintains anantithrombotic surface.

1.

Antithrombin III (AT III). AT III binds to and inhibits Factor Xa and thrombin. The sulfatedglycosamino-glycans (p. 40) heparan sulfate and heparin enhance the binding of AT III to Factor Xaor to thrombin, thus inhibiting coagulation. Heparan sulfate is present on the external surface of mostcells, including endo-thelial surfaces. Mast cells and basophils release heparin.

2.

Thrombomodulin. A glycosaminoglycan product of endothelial cells, thrombomodulin can form acomplex with thrombin, thereby removing thrombin from the circulation and inhibiting coagulation. Inaddition, thrombomodulin also binds protein C.

3.

Protein C. After protein C binds to the thrombomod-ulin portion of the thrombin-thrombomodulin4.

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complex, the thrombin activates protein C. Activated protein C (Ca) is a protease. Together with itscofactor protein S, Ca inactivates the cofactors Va and VIIIa, thus inhibiting coagulation.Protein S. This is the cofactor of protein C and is thus an anticoagulant.5.

Fibrinolysis Breaks Up Clots

As noted on page 425, cross-linked stable fibrin traps red and white blood cells as well as platelets in afreshly formed thrombus. Through the interaction of actin and myosin in the platelets, the clot shrinks to aplug and thereby expels serum. After plug formation, fibrinoly-sis- the breakdown of stable fibrin - breaksup the clot in a more general process known as thrombolysis. As shown in Figure 17-25, the process offibrinolysis begins with the conversion of plasminogen to plasmin, catalyzed by one of two activators:tissue-type plasminogen activator or urokinase-type plasminogen activator. Table 17-2 summarizes theproperties of fibrinolytic factors.

The source oftissue plasminogen activator(t-PA), a serine protease, is endothelial cells. t-PA consists ofa single peptide chain with two "kringles" at the N-terminal portion of the molecule and a protease motif inthe C-terminal portion. Kringles are loop structures created by three disulfide bonds and serve to anchor themolecule to its substrate. t-PA converts the plasma zymogen plasmino-gen to the active fibrinolyticprotease plasmin. The presence of fibrin greatly accelerates the conversion of plas-minogen to plasmin.

Besides t-PA, the other plasminogen activator, uroki-nase-type plasminogen activator(u-PA), is presentin plasma either as a single-chain protein or as the two-chain product of a proteolytic cleavage. Like t-PA,u-PA converts plasminogen to the active protease plasmin. However, this proteolysis requires that u-PAattaches to a receptor on the cell surface called urokinase plasminogen activator receptor (u-PAR).

Plasminogen is a large, single-chain glycoprotein that is composed of an N-terminal heavy chain (A chain)and a C-terminal light chain (B chain). The N-terminal heavy chain contains five kringles, and the C-terminallight chain contains the protease domain. t-PA cleaves plasmin-ogen at the junction between the heavy andlight chains, yielding plasmin. However, the two chains in plasmin remain connected by disulfide bonds.

Plasmin is a serine protease that can break down both fibrin and fibrinogen. The five kringles of the heavychain of plasminogen are still present in plasmin. These anchors attach to lysine residues on fibrin, holding

the protease portion of the molecule in place to promote hydrolysis. Plasmin proteolytically cleaves stablefibrin to fibrin breakdown products. Plasmin can also cleave t-PA between the kringle and protease motifisof t-PA. The C terminus of single-chain t-PA nonetheless retains its protease activity.

Figure 17-25 The fibrinolytic cascade. The abbreviations are listed in Table 17-2 on the following page.

page 446G

Table 17-2. FIBRINOLYTIC FACTORS

NAME ALTERNATENAMES

PROPERTIES

Tissue-type plasminogenactivator

t-PA A serine protease that catalyzes hydrolysis of plasminogen at the junction between the N-terminalheavy chain and C-terminal light chainN terminus contains two loop structures calledkringles

Urokinase-typeplasminogen activator

u-PA A serine protease

Urokinase-typeplasminogen activator

receptor

u-PAR Binds to and required for the activity of u-PA

Plasminogen Single-chain plasma glycoprotein with largeN-terminal and small C-terminal domain.N terminus contains five kringles

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Plasmin Fibrinolysin A serine protease

Plasminogen activatorinhibitor-1

PAI-1 A serpin (serine protease inhibitor)In plasma and plateletsForms 1:1 complex with t-PA in blood

Plasminogen activatorinhibitor-2

PAI-2 A serpin (serine protease inhibitor)Detected only in pregnancy

2-Antiplasmin 2-AP A serpin (serine protease inhibitor)

Forms 1:1 complex with plasmin in blood

The cardiovascular system regulates fibrinolysis at several levels, using both enhancing and inhibitorymechanisms. Catecholamines and bradykinin increase the levels of circulating t-PA. Two serinep roteaseinhibitors ("ser-pins") reduce the activity of the plasminogen activators: plasminogen activator inhibitor-1(PAI-1) and plasmino-gen activator inhibitor-2 (PAI-2). PAI-1 complexes with and inhibits both single-chain

and two-chain t-PA. PAI-2 mainly inhibits u-PA. It is of interest that activated protein C, which inhibitscoagulation as shown in Figure 17-24, also inhibits PAI-1 and PAI-2, thereby facilitating fibrinolysis. Only

one serpin targets plasmin, 2-antiplasmin (2-AP). When plasmin is not bound to fibrin (i.e., when the

plasmin is in free solution), 2-AP complexes with and thereby readily inactivates plasmin. However, when

plasmin is attached to lysine residues on fibrin, this inhibition is greatly reduced. In other words, the verypresence of a clot (i.e., fibrin) promotes the breakdown of the clot (i.e., fibrinolysis).

References

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Lassen NA, Henriksen O, Sejrsen P: Indicator methods for measurement of organ and tissue blood flow. In Handbook of Physiology,Section 2: The Cardiovascular System, Vol III. Bethesda, MD, American Physiological Society, 1979, pp. 21-63.

Levine RA, Gillam LD, Weyman AE: Echocardiography in cardiac research. In Fozzard HA, Haber E, Jennings RB, et al (eds): The Heartand Cardiovascular System. New York, Raven Press, 1986, pp 369-452.

Maeda N, Shiga T: Velocity of oxygen transfer and erythrocyte rheology. News Physiol Sci 9:22-27, 1994.

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Poiseuille JLM: Recherches exprimentales sur le mouvement des liquides dans les tubes de trs petits diamtres. Mm SavantEtrangers Paris 9:433-544, 1846.

Reynolds O: An experimental investigation of the circumstances which determine whether the motion of water shall be direct or sinusoid,and of the law of resistance in parallel channels. Philos Trans R Soc Lond B Biol Sci 174:935-982, 1883.

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