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2312 Part XII: Hemostasis and Thrombosis Chapter 135: Fibrinolysis and Thrombolysis 2313

upon infusion of Lys-Plg. 279,280 In a study of a Japanese cohort, approx- the amino acid composition and apparent molecular mass of neonatal
imately 27 percent of individuals with type II deficiency had a clini- Plg are indistinguishable from those of the adult protein, 300,301 plasma
cal history of thrombosis, but it is not clear whether there were other concentrations of Plg in the neonate are approximately 50 to 75 percent
explanations for thrombophilia in these individuals. Acquired Plg of those observed in adults. 300,302,303 On the other hand, levels of histi-
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deficiency may occur in liver disease, sepsis, and Argentine hemor- dine-rich glycoprotein, a carrier protein that may limit Plg’s interaction
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rhagic fever due to decreased synthesis and/or increased catabolism, with fibrin, are also reduced by 50 to 80 percent in healthy, term new-
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but associated thrombosis may be due to abnormalities in other hemo- borns. Neonatal Plg is heavily glycosylated, less readily activated by
static factors in these very ill patients. Similarly, there are no reported t-PA, and only weakly bound to the endothelial cell surface. Through-
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cases of complete t-PA or u-PA deficiency in humans, and no mutations out childhood, global plasma fibrinolytic activity and plasmin genera-
or polymorphisms in these genes have so far been clinically linked to tion are decreased in comparison to adults, and this relative deficiency
thrombophilia. Defects in Plg activator release, as well as increased inhi- may contribute to the high frequency of thrombosis associated with
bition of t-PA by PAI-1, have been reported in associated with thrombo- central venous line placement, Kawasaki disease, and Henoch-Schönlein
sis, 283,284 and with chronic renal disease and hypertension. 81,83 purpura in this age group. 305
Global deficiency in fibrinolytic function, moreover, is associated Although t-PA antigen and activity levels are reduced by 50 to
with increased risk for venous thrombosis, as well as first myocardial 75 percent compared with adult values throughout childhood, stressed
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infarction in young men. 285,286 Increased circulating PAI-1 appears to infants, such as those with severe congenital heart disease or respiratory
represent an independent risk factor for vascular reocclusion in young distress syndrome, may have t-PA antigen levels that are increased by up
survivors of myocardial infarction. In addition, increased levels to eightfold because of the t-PA release response. 306,307 In contrast, the
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of PAI-1 have been associated with deep vein thrombosis in patients principal plasmin inhibitors undergo only minimal change from birth to
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undergoing hip replacement surgery and in individuals with insu- adulthood. 302,308–310 Thus, reduced fibrinolytic activity may contribute to
lin resistance. Although a 4G versus 5G polymorphism in the PAI-1 the thrombogenic state commonly observed in the newborn, but this
311
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promoter has been reported, the 4G form being associated with higher predilection may be reversed under conditions of physiologic stress.
PAI-1 plasma levels, it is not yet established as to whether this allele cor-
relates with elevated thrombotic risk. 290,291 With regard to such studies, FIBRINOLYTIC ACTIVITY DURING PREGNANCY
one should bear in mind that PAI-1 is itself an acute phase reactant, and
thus may not be directly responsible for the observed prothrombotic AND PUERPERIUM
tendency. 292 Pregnancy is a hypofibrinolytic state. 312–314 Both Plg and fibrinogen lev-
els in plasma increase by 50 to 60 percent in the third trimester. How-
ENHANCED FIBRINOLYSIS AND BLEEDING ever, overall fibrinolytic activity, as reflected in euglobulin lysis activity,
is reduced, and increased fibrin deposition is suggested by increasing
Enhanced fibrinolysis resulting from congenital or acquired loss of D-dimer levels throughout pregnancy. Between the 20th week of
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fibrinolytic inhibitor activity may be associated with a bleeding diath- pregnancy and term, PAI-1 levels increase to three times their normal
esis. Patients with congenital deficiency of α -PI may present with level, while PAI-2 levels rise to 25 times their level in early pregnancy.
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312
2
a severe hemorrhagic disorder as a result of impaired inactivation Less dramatic increases in both u-PA and t-PA levels are also observed.
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of plasmin and premature lysis of the hemostatic plug. Acquired Within 1 hour of delivery, however, concentrations of both PAI-1 and
α -PI deficiency may be seen in patients with severe liver disease from PAI-2 begin to decrease, and return to normal within 3 to 5 days. 312
2
decreased synthesis, disseminated intravascular coagulation from con- In preeclampsia, the hemostatic and fibrinolytic imbalances seen
sumption, nephrotic syndrome from urinary losses, or during throm- in pregnancy are further exaggerated. Circulating PAI-1 levels exceed
316
294
bolytic therapy, which induces excessive utilization of the inhibitor. those in normal pregnancy, and fibrin deposition is seen in the glom-
TAFI levels are markedly reduced in liver cirrhosis, correlating with erular capillaries and spiral arteries of the placenta. Interestingly, levels
enhanced plasma fibrinolysis, and serving as an independent predictor of PAI-2, a marker of placental function, are reduced during preec-
of mortality. 295 lampsia compared with normal pregnancy, and this decrease correlates
Patients with acute promyelocytic leukemia demonstrate excessive with intrauterine growth retardation of the fetus. Elevated TAFI levels
expression of annexin A2 on their developmentally arrested promyelo- may be a cause of fibrin deposition and occlusion of placental vessels in
cytes. Bleeding in this disorder is accompanied by evidence of high lev- preeclampsia. 317
els of plasmin generation and depletion of α -PI. Bleeding resolves upon
2
initiation of all-trans-retinoic acid therapy, which eliminates expression
of promyelocyte annexin A2, probably through a transcriptional mech- FIBRINOLYTIC THERAPY
anism. In this setting, A2 acts most likely in concert with S100A10, The goal of thrombolytic therapy is rapid restoration of flow to an
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which is also upregulated in an acute promyelocytic leukemia (APL) occluded vessel achieved by accelerating fibrinolytic proteolysis of the
cell line. 201,296 thrombus. The fibrinolytic system functions physiologically to remove
318
Complete loss of PAI-1 expression resulting in hemorrhage in a fibrin deposits through the action of plasmin, but this is often too slow
9-year-old child was associated with severe hemorrhage in the setting of to prevent tissue injury following acute vascular occlusion. Because arte-
297
trauma or surgery. This autosomal recessive trait reflected a frameshift rial thrombosis immediately renders distal tissue ischemic with rapid
mutation within exon 4 that induced a premature stop codon. This case onset of dysfunction and necrosis, a critical problem is minimizing time
demonstrates that PAI-1 is a central regulator of fibrinolysis in humans.
to restoration of flow. Thrombolytic therapy should be viewed as one
part of an overall antithrombotic plan that frequently includes antico-
DEVELOPMENTAL REGULATION OF THE agulants, antiplatelet agents, and mechanical approaches, all designed
FIBRINOLYTIC SYSTEM to rapidly restore flow, prevent reocclusion, and promote healing. Here
we review thrombolytic approaches to stroke and peripheral vascular
In the resting, nonstressed state, the plasmin–generating potential in disease. Thrombolytic therapy for deep vein thrombosis, pulmonary
the newborn is significantly less than that of the adult. 298,299 Although embolism, and myocardial infarction are discussed elsewhere.

Kaushansky_chapter 135_p2303-2326.indd 2312 9/18/15 5:13 PM