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1976 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1977

LIPOPROTEIN(A) annexin A2-deficient mice, and was overcome upon intravenous infu-
Lp(a) is a low-density lipoprotein (LDL)-like particle that is an inde- sion of unmodified annexin A2. 228
pendent risk factor for atherosclerosis. 195–197 In addition to the apolipo-
protein B-100 found on LDL, Lp(a) contains a disulfide-linked moiety ANTIPHOSPHOLIPID SYNDROME
called apolipoprotein(a) [apo(a)]. Apo(a) shares a remarkable degree of Antiphospholipid syndrome (APS) is an autoimmune disorder char-
homology with plasminogen, as it possesses multiple tandem repeats acterized by thrombosis, recurrent pregnancy loss, and persistently
of a kringle IV-like domain, a single domain resembling kringle V, and positive antiphospholipid antibodies. 229,230 Compared to patients
a pseudoprotease domain. 198,199 Plasminogen and apo(a), furthermore, with lupus erythematosus, nonimmune thrombosis, or healthy con-
are closely linked on chromosome 6 and appear to have arisen from a trols, a relatively high proportion of patients with APS and severe
common ancestral gene. 200 thrombosis (22 percent) has antibodies directed against annexin A2.
Whereas Lp(a) levels are only transiently responsive to diet, 201,202 Antiannexin A2 antibodies may block t-PA–dependent cell-surface
plasma levels appear to be subject to mendelian inheritance. 203–205 plasmin generation, and also induce expression of procoagulant mol-
Plasma Lp(a) concentrations correlate inversely with the ratio of kringle ecules, such as TF. These events may require crosslinking of β -GPI
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IV to kringle V encoding domains within the apo(a) gene, 206,207 such that bound to closely associated cell-surface A2, 231,232 and signaling via
larger apo(a) gene products are associated with lower plasma concen- myeloid differentiation protein 88 (MyD88) and nuclear factor kappa
trations of apo(a). In addition, Lp(a) is an acute phase reactant in the B (NFκB)-dependent pathway. Additional evidence shows that A2
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postsurgical and post–myocardial infarction setting, and in patients is required for the pathogenic effects of antiphospholipid antibodies
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with cancer, suggesting a role for soluble inflammatory mediators in in mice. High-titer antiannexin A2 antibodies are also associated
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regulating its synthesis or assembly. Apo(a) possesses a high-affinity with cerebral vein thrombosis in patients without the full diagnostic
lysine binding site within kringle 4 that closely resembles that of krin- criteria for APS. 153
gle 1 of plasminogen, and kringle 37 of the originally cloned apo(a)
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resembles the lysine-binding plasminogen kringle 4 of plasminogen.
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In vivo, Lp(a) colocalizes histologically with fibrin in atheromatous ROLE OF ADHESION MOLECULES
tissue. 210
When apo(a) is overexpressed in transgenic mice, cell-associated A proinflammatory environment is also prothrombotic. Endothelial
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plasmin activity is reduced such that the animals are resistant to t-PA cells express molecules that regulate binding of leukocytes to their sur-
thrombolysis. Three potential explanations for the prothrombotic, face during inflammation. These interactions have both direct and indi-
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proatherogenic effect of Lp(a) include (1) the observation that both rect roles in hemostasis and thrombosis, and, in some cases, interactions
Lp(a) and apo(a) inhibit Lys-plasminogen binding to endothelial cells of leukocytes and platelets with inflamed endothelial cells feed forward
(half-maximal inhibitory dose [ID ] = 36-fold excess), and to annexin to promote thrombosis. Moreover, the inflammatory response itself
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50
A2, with affinity similar to that for plasminogen 215–217 ; (2) endothe- results in the expression of adhesion molecules and mediators that sec-
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lial cell exposure to Lp(a) in vitro enhances expression of PAI-1 ; and ondarily promote hemostasis. In addition, membrane microparticles
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(3) Lp(a) may act as a competitive inhibitor of t-PA in the presence of derived from platelets, leukocytes, and perhaps endothelium, provide
fibrinogen, or as an uncompetitive inhibitor of the fibrin-dependent circulating sources of TF, proinflammatory lipids, and other molecules
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enhancement of t-PA–induced plasmin generation. Overexpression that have the potential to regulate thrombosis and inflammation at a
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of Lp(a) in mice receiving a high-fat diet results in atherosclerosis-like distance from the primary site. 236–240
lesions containing anti-apo(a) cross-reactive material. Deposition of
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both lipid and apo(a) was reduced in mice expressing apo(a) in which
lysine binding sites had been mutated. Thus, lysine binding sites of MOLECULAR CHANGES IN AN
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apo(a) appear to allow it to compete with plasminogen for cell surface INFLAMMATORY MILIEU
receptors, thereby increasing atherogenicity.
IMMEDIATE CHANGES
HOMOCYSTEINE Either histamine or thrombin produced locally at the site of inflam-
Homocysteine is a thiol-containing amino acid that accumulates in mation by degranulation of resident tissue mast cells stimulates the
nutritional deficiencies of vitamin B , vitamin B , or folic acid, or in overlying endothelial cells to express P-selectin on their surfaces.
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12
inherited abnormalities of cystathionine β-synthase, methylene tetrahy- This change occurs within minutes and is caused by the rapid fusion of
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drofolate reductase, or methionine synthase. Multiple studies have Weibel-Palade bodies, with the plasma membrane bringing P-selectin to
shown homocysteine to be an independent risk factor for atherosclero- the surface. Along with P-selectin expression, fusion of the Weibel-Palade
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sis, venous thromboembolism, and death. Homocysteine lowering bodies also results in the release of VWF into the local environment.
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in patients with inborn errors of homocysteine metabolism leads to a P-selectin serves as a leukocyte receptor for P-selectin glycoprotein
striking reduction in cardiovascular morbidity, but supplementation ligand (PSGL)-1, L-selectin, and other ligands. PSGL-1 is a specific
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with B vitamins in patients with established cardiovascular disease is sialomucin containing sialylated, fucosylated O-linked oligosaccharides
of no benefit. In vitro, homocysteine-treated endothelial cells bound as well as an unusual sulfated tyrosine residue motif. Dimerization of
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approximately 50 percent less t-PA than untreated cells, and activated PSGL-1 is required for optimal recognition of P-selectin. Adhesive
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approximately 50 percent less plasminogen. Mass spectrometry interactions between P-selectin and its ligands result in the tethering
studies indicate that homocysteine directly disables the t-PA binding of passing leukocytes to, and rolling on, the surface of the endothelial
domain of annexin A2 by forming a covalent adduction product with cell as the first step in leukocyte emigration. PSGL-1 also interacts with
cysteine 9 within the tail domain of purified annexin A2, thus inhibit- P-selectin expressed on platelets that have become activated and adher-
227
ing its ability to bind t-PA. Mice on a high homocysteine-generating ent to endothelium. 45,245 L-selectin, another member of the selectin fam-
diet, moreover, displayed dysfunctional annexin A2, and loss of both ily, is constitutively expressed on most leukocytes. It binds to sialylated,
fibrinolytic and angiogenic potential. This phenotype mimicked that of fucosylated GP ligands expressed by endothelial cells in response to
Kaushansky_chapter 115_p1967-1984.indd 1976 9/18/15 10:09 AM