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2310 Part XII: Hemostasis and Thrombosis Chapter 135: Fibrinolysis and Thrombolysis 2311

Figure 135–3. Degradation of fibrinogen and crosslinked fibrin by plasmin. Top panel: On fibrinogen, plasmin initially cleaves the C-terminal
regions of the α and β chains within the D domain, releasing the Aα and Bβ fragments. In addition, a fragment containing fibrinopeptide B (FPB)
from the N-terminal region of the β chain is released giving rise to the intermediate fragment known as “fragment X.” Subsequently, plasmin cleaves
the three connecting polypeptide chains connecting D and E domains, giving rise to fragments D, E, and Y. Bottom panel: Upon polymerizatoin by
thrombin, fibrinogen forms fibrin. When degrading crosslinked fibrin, plasmin initially cleaves the C-terminal region of the α and β chains within the
D domain. Subsequently, some of the connecting regions between the D and E domains are severed. Fibrin is ultimately solubilized upon hydrolysis
of additional peptide bonds within the central portions of the coiled–coil connectors, giving rise to fibrin degradation products such as D-dimer.
(Reproduced with permission Nathan DG, Orkin SH, Ginsburg D, et al: Hematology of Infancy and Childhood. 6th edition. Philadelphia, PA: WB Saunders;
2003.)

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carboxyl–terminal fragments from the α chain within the D domain of bradykinin, chemotaxis, and immune modulation, have been
of fibrinogen (Aα fragment). 205–208,215–218 . Simultaneously, but more ascribed to fibrin breakdown products.
slowly, the N–terminal segments of the β chains are cleaved, releasing
a peptide containing fibrinopeptide B. The resulting Mr approximately
250,000 molecule is termed fragment X and represents a clottable form TISSUE-TYPE PLASMINOGEN ACTIVATOR –
of fibrinogen. Additional cleavage events may release the Bβ fragment
from the β chain’s carboxyl–terminus, and, in a series of subsequent MEDIATED PLASMINOGEN ACTIVATION
reactions, plasmin cleaves the three polypeptide chains that connect With or without fibrin, t-PA–mediated activation of Plg follows
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the D and E domains giving rise to free D domain (Mr ~100,000) plus Michaelis–Menten kinetics. In the absence of fibrin, t-PA is a weak
the binodular D–E fragment known as fragment Y (Mr ~150,000). activator of Plg. However, in the presence of fibrin, the catalytic effi-
Finally, domains D and E are separated from each other, and some of ciency (k /K ) of t-PA–dependent Plg activation is enhanced by
cat
m
the N–terminal fibrinopeptide A sites on domain E are also modified. approximately 500-fold. This is the basis for its specificity as a lytic agent
Although fragment X can be converted to fibrin by thrombin, the frag- in the treatment of thrombosis. The affinity between t-PA and Plg in
ments Y, D, and E are all nonclottable, and, in fact, may inhibit poly- the absence of fibrin is low (K 65 μM), but increases significantly in its
m
merization of fibrinogen. 219 presence (K 0.16 μM), even though the catalytic rate constant remains
m
–1
essentially unchanged (kcat ~0.05 sec ). When plasmin forms on the
Fibrin fibrin surface, both its lysine binding sites and its active site are occupied.
Plasmin degradation of fibrin leads to a distinct set of molecular prod- Thus, it is relatively protected from its physiologic inhibitor, α -PI. 225
2
ucts (see Fig. 135–3). Species similar to fragments Y, D, and E, but The interaction of t-PA with fibrin is probably initiated by its “fin-
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lacking fibrinopeptide sites, are released from noncrosslinked fibrin. ger” domain. However, once fibrin is modified by plasmin, carboxy-
If fibrin has been extensively crosslinked by factor XIII, however, the terminal lysine residues are generated, and these become binding sites
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resulting D fragments are crosslinked to an E domain fragment. Assay for “kringle” 2 of t-PA and “kringles” 1 and 4 of Plg. Therefore, fibrin
of crosslinked D–dimer fragments is employed clinically to identify dis- accelerates its own destruction by (1) enhancing the catalytic efficiency
seminated intravascular coagulation–like states associated with exces- of plasmin formation by t-PA, (2) protecting plasmin from its physio-
sive plasmin–mediated fibrinolysis. Several biologic activities, including logic inhibitor, α -PI, and (3) providing new binding sites for Plg and
2
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inhibition of platelet function, potentiation of the hypotensive effects t-PA once its degradation has begun.

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