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CHAPTER 135 plasminogen in adults is approximately 2 days. Its 791 amino acids are
7
crosslinked by 24 disulfide bridges, 16 of which give rise to five homol-
FIBRINOLYSIS AND ogous triple loop structures called “kringles” (Fig. 135–2). The first
8
(K1) and fourth (K4) of these 80–amino-acid, Mr approximately 10,000
9
THROMBOLYSIS structures impart high- and low-affinity lysine binding, respectively.
The lysine–binding domains of plasminogen appear to mediate its spe-
cific interactions with fibrin, cell surface receptors, and other proteins,
including its circulating inhibitor α –plasmin inhibitor (α -PI). 10–14
2
2
Katherine A. Hajjar and Jia Ruan Posttranslational modification of plasminogen results in two
glycosylation variants (forms 1 and 2; see Table 135–1). 15–17 O–linked
oligosaccharide, consisting of sialic acid, galactose, and galactosamine
SUMMARY resident on Thr345, is common to both forms. Only form 2, however,
contains N–linked oligosaccharide on Asn 288 that is comprised of sialic
acid, galactose, glucosamine, and mannose. The carbohydrate portion
Improved understanding of the molecular mechanisms of fibrinolysis has led of plasminogen appears to regulate its affinity for cellular receptors, and
to major advances in fibrinolytic and antifibrinolytic therapy. Characterization may also specify its physiologic degradation pathway.
of the genes for all the major fibrinolytic proteins has revealed the structure of Activation of plasminogen results from cleavage of a single Arg–
the relevant serine proteases, their inhibitors, and their receptors. The devel- Val peptide bond at position 560–561, giving rise to the active pro-
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opment of genetically engineered animals deficient in one or more fibrinolytic tease, plasmin (see Table 135–1). Plasmin contains a typical serine
protein(s) has revealed both expected and unexpected functions. In addition, protease catalytic triad (His 602, Asp 645, and Ser 740), but exhibits
we now have a catalog of acquired and inherited disorders reflective of either broad substrate specificity when compared to other proteases of this
18
fibrinolytic deficiency with thrombosis or fibrinolytic excess with hemorrhage. class. The circulating form of plasminogen, aminoterminal glutamic
These advances have led to development of more effective and safer protocols acid plasminogen (Glu–Plg), can be converted by limited proteolysis to
for both pro- and antifibrinolytic therapy in a variety of circumstances. several modified forms known collectively as Lys–Plg. 19,20 Hydrolysis of
the Lys77–Lys78 peptide bond gives rise to a conformationally modi-
fied form of the zymogen that more readily binds fibrin, displays two-
BASIC CONCEPTS OF FIBRINOLYSIS to threefold higher avidity for cellular receptors, and is activated 10 to
20 times more rapidly than Glu-Plg 11,21,22 Lys–Plg does not normally
In response to vascular injury, fibrin, the insoluble end product of circulate in plasma, but has been identified on cell surfaces. 23,24
21
the action of thrombin on fibrinogen, is deposited in blood ves- Spanning 52.5 kb of DNA on chromosome 6q26–27, the Plg gene
sels, thus stemming the flow of blood. Once the vessel has healed, the consists of 19 exons 25,26 and directs expression of a 2.7-kb mRNA
8
fibrinolytic system is activated, converting fibrin to its soluble deg- (see Fig. 135–2). The 5′ upstream region of the Plg gene contains two reg-
radation products through the action of the serine protease, plasmin ulatory elements common to genes for acute–phase reactants (CTGGGA)
(Fig. 135–1A). Fibrinolysis is subject to precise control because of the and six interleukin (IL)-6 response elements. Plg gene activity, more-
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actions of multiple activators, inhibitors, and cofactors. In addition, over, is stimulated by the acute-phase-mediator IL-6 both in vitro and
1
receptors expressed by endothelial, monocytoid, and myeloid cells pro- in vivo. The gene is closely linked and structurally related to that of
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vide specialized, protected environments where plasmin can be generated apolipoprotein(a), an apoprotein associated with the highly atherogenic
without compromise by circulating inhibitors (Fig. 135–1B). Beyond low density lipoprotein–like particle lipoprotein(a), and more distantly
2,3
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its more traditional role in fibrin degradation, the fibrinolytic system related to other kringle-containing proteins such as tissue-type plas-
also supports a variety of tissue remodeling mechanisms. This chapter minogen activator (t-PA), urokinase-type plasminogen activator (u-PA),
reviews the fundamental features of plasmin generation, considers the macrophage-stimulating protein, and hepatocyte growth factor. 29–34
major clinical syndromes resulting from abnormalities in fibrinolysis,
and discusses approaches to fibrinolytic and antifibrinolytic therapy. The Physiologic Functions of Plasmin(ogen)
Mice made completely deficient in Plg through gene targeting undergo
COMPONENTS OF THE FIBRINOLYTIC normal embryogenesis and development, are fertile, and survive to
35,36
SYSTEM adulthood (Table 135–2). These animals display runting and ligne-
ous conjunctivitis, and harbor spontaneous thrombi in the liver, stom-
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ach, colon, rectum, lung, and pancreas, as well as fibrin deposition in
PLASMINOGEN the liver and ulcerative lesions in the gastrointestinal tract and rectum.
Synthesized primarily in the liver, plasminogen is a Mr approximately These results suggested that Plg is not strictly required for normal devel-
4,5
92,000 single–chain proenzyme that circulates in plasma at a concen- opment, but does play a central role in fibrin homeostasis. In humans,
tration of approximately 1.5 μM (Table 135–1). The plasma half-life of Plg deficiency presents most often with ligneous mucositis as a result of
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fibrin deposition, and is rarely a cause of macrovascular thrombosis (see
Fibrinolytic Deficiency and Thrombosis below).
Acronyms and Abbreviations: α -PI, alpha-2 plasmin inhibitor; APL, acute
2
promyelocytic leukemia; IL, interleukin; MMP, matrix metalloproteinase; PLASMINOGEN ACTIVATORS
Plg, plasminogen; PAI, plasminogen activator inhibitor; TAFI, thrombin- Tissue-Type Plasminogen Activator
activatable fibrinolysis inhibitor; TGF-β, transforming growth factor beta; One of two major endogenous Plg activators, t-PA consists of 527
t-PA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen amino acids comprising a glycoprotein of Mr approximately 72,000
activator; uPAR, urokinase-type plasminogen activator receptor. (see Table 135–1). t-PA contains five structural domains including a
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fibronectin–like “finger,” an epidermal growth factor–like domain, two

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