Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3793_Библиотеки_им_академика_М_И_Перельмана
.pdf
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 79
https://t.me/medicina_free
site of vascular injury without producing significant flow disturbance within the vessel. After a significantly strong thrombogenic stimulus (i.e., deep vessel injury), however, massive
platelet activation with subsequent fibrin deposition may
overwhelm the intrinsic fibrinolytic system and cause thrombus
formation, thrombus growth, and vessel vasospasm that leads
to a significant reduction in blood flow.
Factors That Influence Thrombus Formation
Several local and systemic factors present at the time of plaque
rupture may influence the degree and duration of thrombus
deposition after vessel wall injury. Interaction of these factors
may account for the different pathologic and clinical manifestations of acute coronary syndromes.
Local Factors
Degree of vessel wall injury. The degree of vessel wall injury
plays an important role in the biochemical response to plaque
rupture. With mild amounts of vascular injury (superficial type
III vascular damage), platelet adherence reaches a maximum
within 5 to 10 minutes and results in a thrombus that can be
dislodged by flowing blood. In contrast, deep vessel injury (deep
type III injury) with exposure of fibrillar collagen results in
markedly enhanced platelet deposition and thrombus formation
that cannot be dislodged even at increased shear rates.66 Tissue
factor exposed by deeper injury likely contributes to the increased
thrombogenicity by activating the extrinsic coagulation system.
Degree of stenosis. The amount of platelet adherence is also
determined by their transport into the injured area.63 Transport
of platelets is determined by the shear rate, which is the difference
in blood velocity between the center of the vessel and along the
vessel wall. Shear rates increase with decreasing vessel diameter
(i.e., increased stenosis) and with increasing flow. In vitro studies
mimicking mild vascular injury with exposure of de-endothelialized
vessels to low shear rates show the adherence of only a single
layer of platelets. With the same amount of injury, but at higher
shear rates, the initial platelet deposition rate and maximal extent
of deposition are significantly increased.
The degree of stenosis may influence the severity of thrombus
formation by other mechanisms. That platelet deposition is greater
with increasing amounts of stenosis suggests that platelet activation may be induced by shear forces generated by the sudden
change in vessel geometry.68 In addition, the flow characteristics
of blood through the atherosclerotic lesion are partly determined
by the extent of diameter stenosis. Flow is accelerated as blood
passes through a stenosis and decelerates distal to the lesion.
The sudden deceleration induces flow separation and recirculation
vortices. The high shear rate area (the stenosis) favors platelet
deposition, whereas the low shear rate area (the poststenotic
recirculation zone) favors the deposition of fibrin. The combination of higher shear rates with large changes in flow dynamics
seen in the more severely stenotic vessels results in a thrombus
that is richer in platelets at the apex and contains larger amounts
of fibrin distally.63 These platelet-rich regions may be less amenable
to fibrinolysis.
69
Residual thrombosis. The presence of residual thrombus
predisposes to recurrent thrombotic vessel occlusion by two
67
mechanisms. The residual thrombus may encroach into the vessel
lumen and cause a more stenotic lesion with increased shear
rates, which may lead to further platelet activation and deposition.66 Residual thrombus is a powerful thrombogenic stimulus.
The degree of platelet deposition is increased twofold to fourfold
on the surface of residual thrombi compared with on the surface
of deeply injured arterial walls,70 and the thrombi continue to
grow despite heparin treatment.71 Residual thrombi may offset
the effects of the natural fibrinolytic system and add to the extent
of thrombosis after plaque rupture.
Systemic Factors. Experimental and clinical studies suggest
that primary hypercoagulability can enhance thrombus formation.
In this model, after plaque disruption, individuals with one or
two “thrombogenic risk factors” may form a small amount of
thrombus that is clinically silent. In other individuals with more
prothrombotic risk factors, a larger thrombus may be formed
after the same degree of vessel injury, resulting in a more occlusive
lesion that may produce unstable angina or acute MI.
72
The level of circulating catecholamines at the time of plaque
disruption may have important consequences. Platelet aggregation
and thrombin generation can be promoted by catecholamines.68
Such diverse factors as cigarette smoking, emotional state, and
time of day have a direct effect on catecholamine levels and may
provide a link between these clinically recognized risk factors
and acute coronary syndromes.
Metabolic abnormalities—such as the metabolic syndrome
or any of its components, including diabetes, hypertension, and
obesity—may increase thrombogenicity mediated through the
inflammation that they induce. Patients with hypercholesterolemia
show increased platelet reactivity at sites of vascular damage73
and hypercoagulability.74 There is evidence that platelet reactivity
and coagulation are increased in diabetics, suggesting a direct
mechanism for a prothrombotic state that may be responsible
for the increased incidence of MI in these patients.
68
Finally, defective naturally occurring fibrinolysis may contribute to enhanced thrombus formation. High levels of naturally
occurring inhibitors, such as plasminogen-activator inhibitor,75
may predispose to an increased risk of acute coronary syndromes.
High levels of lipoprotein(a) may also be important in ischemic
heart disease. Apolipoprotein(a) is a glycoprotein present in
lipoprotein(a) that has close structural homology with plasminogen.76 This close homology may enable apolipoprotein(a) to act
as a competitive inhibitor of plasminogen and cause a prothrombotic state. In addition, increased levels of other hemostatic
proteins, such as fibrinogen and factor VII, have been identified
in patients with ischemic heart disease.68 Fibrinogen and factor
VII activity increase with advancing age, obesity, hyperlipidemia,
diabetes, smoking, and emotional stress, all factors associated
with an increased risk of MI.
INTEGRATED PATHOGENESIS OF ACUTE
CORONARY SYNDROMES
The acute coronary syndromes—unstable angina, non–ST elevation MI, ST elevation MI, and sudden cardiac death—all result
from acute reductions in coronary blood flow. In these disease
80 PART II Scientific Foundation of Cardiac Intensive Care
thrombus
https://t.me/medicina_free
processes, atherosclerotic plaque disruption occurs and initiates
a cascade of events that culminates in the formation of a thrombus
overlying the damaged area. After plaque disruption and thrombus
formation, there are different clinical outcomes influenced by
location of the plaque (proximal vs. distal), existence of collaterals,
the extent of the vessel injury, the degree of stenosis, and the
thrombotic-thrombolytic equilibrium at the time of rupture
(Fig. 7.13).
CONCLUSION
Coronary atherosclerosis is the most common cause of ischemic
heart disease. Atherosclerosis without thrombosis is generally a
benign disease, however. Disrupted atheromatous plaques are
commonly associated with the formation of mural or occlusive
thrombi, usually adherent to the area of damage. Certain types
of plaques—those rich in lipids and surrounded by a thin fibrous
cap—are the most prone to rupture. Numerous factors, intrinsic
and extrinsic to the plaque itself, interact to cause the formation
of a vulnerable lesion and, ultimately, plaque disruption. Erosion,
fissuring, or rupturing of plaques play a fundamental role in the
onset of acute coronary syndromes. In addition, repetitive damage
to the plaque with thrombosis and fibrotic organization is
important in the insidious progression of coronary artery disease.
Since the original clinical description of Herrick, much has
been learned concerning the specific mechanisms involved in
the pathophysiology of acute coronary syndromes. As discussed
in subsequent chapters, this improved understanding has led to
the development of treatments directed at specific steps in the
pathogenesis of unstable angina, MI, and sudden cardiac death.
Through these and future advances, physicians and scientists
may hope to make a significant impact on the number one cause
of death worldwide.
The full reference list for this chapter is available at
ExpertConsult.com.
Fig. 7.13 Proposed outcome of atherosclerotic plaque fissuring.
Left panel: Initial plaque fissure. Upper right panel: Fissure is
sealed, and the incorporated thrombus undergoes fibrotic
organization, contributing to the progression of coronary artery
disease. Middle right panel: Fissure leads to intraintimal and
intraluminal thrombosis, resulting in partial or transient reduction
of coronary flow as seen in unstable angina. Lower right panel:
Fissure results in occlusive thrombosis, which, if persistent, can
lead to myocardial infarction or sudden ischemic death, particularly
in the absence of collateral flow. (From Davies M, Thomas A.
Plaque fissuring—the cause of acute myocardial infarction, sudden
death, and crescendo angina. Br Heart J. 1985;53:363–373.)
Plaque fissure
Healed fissure:
buried thrombus,
plaque larger
Mural intraluminal
thrombus and
intraintimal thrombus
Occlusive intraluminal
CHAPTER 7 Pathophysiology of Acute Coronary Syndromes 80.e1
https://t.me/medicina_free
REFERENCES
1. AHA Medical/Scientific Statement: prevention: the key to
progress. Circulation. 1993;24:629–632.
2. Murray CJ, Lopez AD. Global mortality, disability, and the
contribution of risk factors. Global Burden of Disease Study.
Lancet. 1997;349:1436–1442.
3. Obstrastzow WP, Straschesko ND. Zur Kenntis der Thrombose
der Koroararterien des Herzens. Z Klin Med. 1910;71:116–132.
4. Herrick JB. Clinical features of sudden obstruction of the
coronary arteries. JAMA. 1912;59:2015–2020.
5. Zhang Y, Cliff WJ, Schoefl GI, Higgins G. Plasma protein
insudation as an index of early coronary atherogenesis. Am J
Pathol. 1993;143:496–506.
6. Johnson-Tidey RR, McGregor JL, Taylor PR, Paston RN. Increase
in adhesion molecule P-selectin in endothelium overlying
atherosclerotic plaques. Am J Pathol. 1994;144:952–961.
7. Davies MJ, Gordon JL, Gearing AJH, et al. The expression of the
adhesion molecules ICAM-1, VCAM-1, DECAM, and E-selectin
in human atherosclerosis. J Pathol. 1993;171:223–224.
8. Farugi RM, DiCorleto PE. Mechanisms of monocyte recruitment
and accumulation. Br Heart J. 1993;69(suppl):S19–S29.
9. Hanson GK. Immune and inflammation mechanisms in
development of atherosclerosis: a perspective for the 1990s.
Nature. 1993;69(suppl):S38–S41.
10. Ross R. The pathogenesis of atherosclerosis: a perspective for the
1990s. Nature. 1993;362:801–809.
11. Rekhter MD, Gordon D. Does platelet-derived growth factor-A
chain stimulate proliferation of arterial mesenchymal cells in
human atherosclerotic plaques? Circ Res. 1994;75:410–417.
12. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond
cholesterol: modification of low-density lipoprotein that
increases its atherogenicity. N Engl J Med. 1989;320:915–924.
13. Ylo-Herttuala S, Rosenfeld ME, Parthasarathy S, et al. Gene
expression in macrophage-rich human atherosclerotic lesions:
15-lipoxygenase and acetyl low density lipoprotein receptor
messenger RNA colocalize with oxidation specific lipid-protein
adducts. J Clin Invest. 1991;87:1146–1152.
14. Demer LL, Watson KE, Bostrim K. Mechanism of calcium in
atherosclerotic lesions. Trends Cardiovasc Med. 1994;4:45–49.
15. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic
mechanisms: oxidation, inflammation and genetics. Circulation.
1995;91:2488–2496.
16. Falk E, Fernandez-Ortiz A. Role of thrombosis in atherosclerosis
and its complications. Am J Cardiol. 1995;75:1B–7B.
17. Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis
of coronary artery disease and the acute coronary syndromes. N
Engl J Med. 1992;326:242–248.
18. Stary HC. Evolution and progression of atherosclerosis in
children and young adults. Arteriosclerosis. 1989;99(suppl
I):I-19–I-32.
19. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J
Med. 1986;314:488–500.
20. Ip JH, Fuster V, Badimon L, et al. Syndromes of accelerated
atherosclerosis: role of vascular injury and smooth cell
proliferation. J Am Coll Cardiol. 1990;15:1667–1687.
21. Parthasarathy S, Wieland E, Steinberg D. A role for endothelial
cell lipoxygenase in oxidative modification of LDL. Proc Natl
Acad Sci USA. 1989;86:1046–1050.
22. Sparrow CP, Parthasarathy S, Steinberg D. Enzymatic
modification of LDL by purified lipoxygenase plus
phospholipase A2 mimics cell-mediated oxidative modification.
J Lipid Res. 1988;29:745–753.
23. Steinbrecher UP, Witzum JI, Parthasarathy S, Kemper HJ. Role of
endothelial cells and their products in the modification of LDL.
Biochim Biophys Acta. 1986;878:49–64.
24. Steinbrecher UP. Oxidation of human LDL results in
derivatization of lysine residues of Apo lipoprotein B by lipid
peroxide decomposition products. J Biol Chem.
1987;262:3603–3608.
25. Parthasarathy S, Fong LG, Otero D, Steinberg D. Recognition
of solubilized apoproteins from delipidated, oxidized LDL by
the acetyl-LDL receptor. Proc Natl Acad Sci USA. 1987;84:
537–540.
26. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively
modified LDL: a potential role in recruitment and retention of
monocyte/macro-phages during atherogenesis. Proc Natl Acad
Sci USA. 1987;84:2985–2988.
27. Min JK, Kim YM, Kwon MC, et al. TNF-related activationinduced cytokine enhances leukocyte adhesiveness: induction of
ICAM-1 and VCAM-1 via TNF receptor-associated factor and
protein kinase C-dependent NF-kappaB activation in endothelial
cells. J Immunol. 2005;175(1):531–540.
28. Navab M, Imes SS, Hama SY, et al. Monocyte transmission
induced by modification of LDL in coculture of human aortic
wall cells is due to the induction of monocyte chemotactic
protein I synthesis and abolished by HDL. J Clin Invest.
1991;88:2039–2040.
29. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of
advanced types of atherosclerotic lesions and a histological
classification of atherosclerosis. A report from the Committee on
Vascular Lesions of the Council on Arteriosclerosis, American
Heart Association. Circulation. 1995;92:1355–1374.
30. MacIsaac A, Thomas JD, Topol EJ. Toward the quiescent
coronary plaque. J Am Coll Cardiol. 1993;22:1228–1241.
31. Falk E, Shah PK, Fuster V. Coronary plaque disruption.
Circulation. 1995;92:657–671.
32. Hangarttner JG, Charleston AJ, Davis MJ, et al. Morphological
characteristics of clinically significant coronary artery stenosis in
stable angina. Br Heart J. 1986;56:54–58.
33. Davies M, Bland J, Hangarttner J, et al. Factors influencing the
presence of acute coronary thrombi in sudden ischaemic death.
Eur Heart J. 1989;10:203–208.
34. Roberts WC, Buja LM. The frequency and significance of
coronary arterial thrombi and other observations in fatal acute
myocardial infarctions: a study of 107 necropsy patients. Am J
Med. 1972;52:425–443.
35. Ridolfi RL, Hutchins GM. The relationship between coronary
artery lesions and myocardial infarction: ulceration of
atherosclerotic plaques precipitating coronary thrombosis. Am
Heart J. 1977;93:468–480.
36. Bini A, Fenoglig JJ, Mesa-Tejada R, et al. Identification and
distribution of fibrinogen, fibrin and fibrin(ogen) degradation
products in atherosclerosis: use of monoclonal antibodies.
Arteriosclerosis. 1989;9:109–121.
37. Smith EB, Keen A, Grant A, Striek C. Fate of fibrinogen in
human arterial intima. Arteriosclerosis. 1990;10:263–275.
38. Constantinides P. Plaque fissures in human coronary thrombosis.
J Atheroscler Res. 1966;6:1–17.
39. Davies MJ, Thomas A. Thrombosis and acute coronary artery
lesions in sudden cardiac ischaemic death. N Engl J Med.
1984;310:1137–1140.
80.e2 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
40. Dewood MA, Spores J, Notske R, et al. Prevalence of total
coronary occlusion during early hours of transmural myocardial
infarction. N Engl J Med. 1980;303:897–902.
41. Davies MJ. A macro and micro view of coronary vascular insult
in ischaemic heart disease. Circulation. 1990;82(suppl
II):II-38–II-46.
42. Davies MJ, Richardson PD, Woolf N, et al. Risk of thrombosis in
human atherosclerotic plaques: role of extracellular lipid,
macrophages and smooth muscle cell content. Br Heart J.
1993;69:377–381.
43. Lundberg B. Chemical composition and physical state of lipid
deposits in atherosclerosis. Atherosclerosis. 1985;56:93–110.
44. Richardson PD, Davies MJ, Born GVR. Influence of plaque
configuration and stress redistribution on fissuring of coronary
atherosclerotic plaques. Lancet. 1989;2:941–944.
45. Burleigh MC, Briggs AD, Lendon CL, et al. Collagen types I and
III, collagen content GAGS and mechanical strength of human
atherosclerotic plaque caps: span-wise variations. Atherosclerosis.
1992;96:71–81.
46. Lendon CL, Davies MJ, Richardson PD. Atherosclerotic plaque
caps are locally weakened when macrophage density is increased.
Atherosclerosis. 1991;87:87–90.
47. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of
intimal rupture or erosion of thrombosed coronary
atherosclerotic plaques is characterized by an inflammatory
process irrespective of the dominant plaque morphology.
Circulation. 1994;89:35–44.
48. Hansson GK, Holm J, Jonasson L. Detection of activated T
lymphocytes in human atherosclerotic plaque. Am J Pathol.
1989;135:169–175.
49. Libby P. Molecular bases of the acute coronary syndromes.
Circulation. 1995;91:2844–2850.
50. Page-McGaw A, Eward AJ, Werb Z. Matrix metalloproteinases
and the regulation of tissue remodeling. Nat Rev Mol Cell Biol.
2007;8:221–223.
51. Henney AM, Wakeley PR, Davies MJ, et al. Localization of
stromelysin gene in expression in atherosclerotic plaques by in
situ hybridization. Proc Natl Acad Sci USA. 1991;88:8154–8158.
52. Vine N, Powell J. Metalloproteinases in degenerative aortic
disease. Clin Sci. 1991;81:233–239.
53. Brown DL, Hibbs MS, Kearney M, et al. Identification of 92 kD
gelatinase in human coronary atherosclerotic lesions. Circulation.
1995;91:2125–2131.
54. Galis Z, Sukhova G, Lark M, Libby P. Increased expression of
matrix metalloproteinases and matrix degrading activity in
vulnerable regions of human atherosclerotic plaques. J Clin
Invest. 1994;94:2493–2503.
55. Lee RT, Kamm RD. Vascular mechanics for the cardiologist. J Am
Coll Cardiol. 1994;23:1289–1295.
56. Cheng GC, Loree HM, Kamn RD, et al. Distribution of
circumferential stress in ruptured and stable atherosclerotic
lesions: a structural analysis with histopathological correlation.
Circulation. 1993;87:1179–1187.
57. Burke AP, Klodgie FD, Farb A, Weber D, Virmani R.
Morphological predictors of arterial remodeling in coronary
atherosclerosis. Circulation. 2002;105:297–303.
58. Lin CS, Panha PD, Zak FG, Lin JC. Morphodynamic
interpretation of acute coronary thrombosis, with special
reference to volcanolike eruption of atheromatous plaque caused
by coronary artery spasm. Angiology. 1988;39:535–547.
59. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque
progression and vulnerability to rupture: angiogenesis as a
source of intraplaque rupture. Arterioscler Thromb Vasc Biol.
2005;25:2054–2061.
60. Mizushige K, Reisman M, Buchbinder M, et al. Atheroma
deformation during cardiac cycle: evaluation by intracoronary
ultrasound. Circulation. 1993;88(suppl I):I-550.
61. Gertz SD, Roberts WC. Hemodynamic shear force in rupture of
coronary arterial atherosclerotic plaques. Am J Cardiol.
1990;66:1368–1372.
62. Hawiger J. Formation and regulation of platelet and fibrin
hemostatic plug. Hum Pathol. 1987;18:111.
63. Fuster V, Badimon L, Cohen M, et al. Insights into the
pathogenesis of acute ischemic syndromes. Circulation.
1988;77:1213–1220.
64. Myler RK, Frink RJ, Shaw RE, et al. The unstable plaque:
pathophysiology and therapeutic implications. J Invasive Cardiol.
1990;2:117–128.
65. Harpel P. Blood protolytic enzyme inhibitors: their role in
modulating blood coagulation and fibrinolytic pathways. In:
Colman RW, Hirsh J, Mardel VJ, Salzman EW, eds. Hemostasis
and Thrombosis: Basic Principles and Clinical Practice. 4th ed.
Philadelphia: Lippincott; 1987:219–234.
66. Badimon L, Badimon JJ, Turitte VT, Fuster V. Platelet thrombus
formation on collagen type I: a model of deep vessel injury:
influence of blood rheology, von Willebrand factor, and blood
coagulation. Circulation. 1988;78:1431–1442.
67. Badimon L, Badimon JJ, Galez A, et al. Influence of arterial wall
damage and wall shear rate on platelet deposition: ex vivo study
in swine model. Arteriosclerosis. 1986;6:312.
68. Fuster V, Badimon L, Badimon JJ, Cheseboro JH. The
pathogenesis of coronary artery disease and the acute coronary
syndromes. N Engl J Med. 1992;326:310–318.
69. Gold H, Yasuda T, Jang I, et al. Animal models for arterial
thrombolysis and prevention of reocclusion: erythrocyte-rich
versus platelet-rich thrombus. Circulation.
1991;83(suppl):IV-26–IV-40.
70. Badimon L, Badimon JJ. Mechanism of arterial thrombosis in
nonparallel streamlines: platelet thrombi grow at the apex of
stenotic severely injured vessel wall: experimental study in the
pig model. J Clin Invest. 1989;84:1134–1144.
71. Badimon L, Badimon JJ, Lassula R, et al. Rethrombosis on an
evolving thrombus is mediated by thrombus-bound thrombin
that is not inhibited by systemic heparin. Thromb Haemost.
1991;65(suppl):321.
72. Fuster V. Mechanisms leading to myocardial infarction: insights
from studies of vascular biology. Circulation. 1994;90:2126–2146.
73. Badimon L, Badimon JJ, Turitte VT, Fuster V. Platelet deposition
at high shear rates is enhanced by high plasma cholesterol levels:
in vivo study in the rabbit model. Arterioscler Thromb.
1991;11:395–402.
74. Hunt BJ. The relationship between abnormal hemostatic
function and the progression of coronary artery disease. Curr
Opin Cardiol. 1990;5:758–765.
75. Olofsson BO, Dahlen G, Nilsson TK. Evidence for increased
levels of plasminogen activator inhibitor and tissue plasminogen
activator in plasma of patients with angiographically verified
coronary artery disease. Eur Heart J. 1989;10:77–82.
76. Rosengren A, Wilhelmsen L, Eriksson E, et al. Lipoprotein (a)
and coronary artery disease: a prospective case-control study in a
general population sample of middle aged men. BMJ.
1990;301:1248–1251.
Regulation of Hemostasis and Thrombosis
https://t.me/medicina_free
OUTLINE
Overview and Definitions, 81
Hemostasis, 81
Necessary Components, 81
Vascular Bed, 81
Extravascular Tissues, 82
Platelets, 82
Coagulation Proteins, 82
Process of Hemostasis, 84
Step 1: Initiation of Coagulation on TF-Bearing Cells, 84
Step 2: Amplification of the Procoagulant Signal by
Thrombin Generated on the TF-Bearing Cell, 84
Step 3: Propagation of Thrombin Generation on the
Platelet Surface, 85
Regulatory Mechanisms to Control Coagulation, 86
Plasma Protease Inhibitors, 86
8
Maureane Hoffman
Endothelial Antithrombotic Mechanisms, 87
Fibrinolysis, 87
Clinical Laboratory Testing, 87
What Can Go Wrong With Hemostasis? 88
Hemorrhage, 88
Consumption of Coagulation Components, 88
Excessive Fibrinolysis, 88
Hypothermia, 88
Acidosis, 88
Thrombosis, 88
Venous Thrombosis, 89
Arterial Thrombosis, 89
What Happens After the Bleeding Stops? 89
OVERVIEW AND DEFINITIONS
Coagulation is the clotting of blood or plasma. Hemostasis is
the process by which bleeding is stopped and is the first component of the host response to injury. Its product is a hemostatic
plug or hemostatic clot. Thrombosis is inappropriate clot formation within an intact vascular structure. Its product is a thrombus.
Thus blood coagulation can occur at a site of injury (hemostasis),
within an intact vessel (thrombosis), or in a test tube, but
hemostasis is a physiologic process that can occur only in a
living, bleeding organism.
Hemostasis consists of primary hemostasis, in which platelets
adhere and are activated at a site of injury, and secondary
hemostasis, in which the initial platelet plug is consolidated in
a meshwork of fibrin. The hemostatic process represents a delicate
and tightly regulated balance between effective activation of local
hemostatic mechanisms in response to injury and control by
regulatory mechanisms that prevent inappropriate activation or
extension of coagulation reactions. The interactions of the protein
components of coagulation can be studied in cell-free plasma
and have been described as a “cascade” of proteolytic reactions.
By contrast, the process of hemostasis occurs on cell surfaces in
a tissue environment and is subject to regulation by a variety of
biochemical and cellular mechanisms. The adequacy of procoagulant levels can be assessed in the routine plasma clotting
assays: the prothrombin time (PT) and activated partial thromboplastin time (aPTT). Platelet number and function can be
assessed in the clinical laboratory. Levels of individual plasma
coagulation inhibitors and other regulatory proteins can also be
assayed. However, there is no laboratory test that can provide
a global assessment of the adequacy of hemostasis or the risk
of thrombosis. Thus each laboratory test gives only a part of
the picture, and the assessment of hemostatic function always
requires that laboratory results be interpreted in the context of
the clinical picture.
HEMOSTASIS
Because hemostasis involves more than simply getting blood to
clot—it must clot at the right time and place and only to the
extent needed to stop bleeding—our understanding of hemostasis
must include a consideration not only of the proteins but also
the cellular and tissue components that are needed to regulate
the coagulation process in vivo.
Necessary Components
Vascular Bed. It is very important that blood not clot within
the vascular system. In the baseline state, vascular endothelial
cells provide a nonthrombogenic interface with the circulating
blood. Endothelial cells do not normally express molecules that
81
CHAPTER 8 Regulation of Hemostasis and Thrombosis 81.e1
https://t.me/medicina_free
Keywords
blood coagulation
thrombosis
bleeding
platelets
thrombin
82 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
support platelet adhesion or promote activation and activity
of the coagulation proteins. In addition, the antithrombotic
features of the endothelial surface go beyond simply being “inert”
with respect to coagulation. The endothelium also expresses
molecules that actively downregulate the coagulation reactions
on its surface: principally thrombomodulin to localize activated
protein C (APC) to the endothelial surface and heparan sulfates
to localize antithrombin (AT) to the endothelial surface. A further
discussion of these mechanisms is presented in the section on
thrombosis. These properties are critical to preventing coagulation
from being initiated at inappropriate sites within the vasculature
and preventing appropriately initiated hemostatic reactions from
spreading within the vascular tree.
Extravascular Tissues. When an injury disrupts a blood vessel,
it allows blood to contact extravascular cells and matrix. Extracellular matrix proteins—such as collagen, fibronectin, thrombospondin, and laminin—interact with adhesive receptors on blood
platelets and support formation of the initial platelet plug at the
site of injury, referred to as primary hemostasis. Perivascular
tissues also express significant levels of tissue factor (TF).
1,2
Exposure of TF to blood initiates the process of thrombin generation on the surfaces of adherent platelets and ultimately leads
to stabilization of the initial platelet plug in a fibrin clot, referred
to as secondary hemostasis. Different tissues express different
complements of matrix components and procoagulants. Thus,
the local tissue environment plays a role in determining the
intensity of the procoagulant response to an injury.
Platelets. Membrane receptors for collagen (glycoprotein [GP]
VI) and other subendothelial and extravascular matrix proteins
are present on the platelet membrane and mediate binding of
unactivated platelets at sites of injury.
3–5
Platelet binding is also
mediated by von Willebrand factor (vWF) bridging between
collagen and the platelet receptor GP Ib. These receptor-binding
events also transmit an activation signal to the platelets. Full
platelet activation also requires stimulation by thrombin that is
produced as the coagulation reactions are initiated. The platelet
surface receptor for fibrinogen, GPIIb/IIIa, rapidly changes
conformation from an inactive to an active form on platelet
activation.
6
This conformational change allows platelet aggregates
to be stabilized by binding to fibrinogen even before conversion
to fibrin begins.
Platelet activation also initiates the synthesis of prostaglandins
and thromboxanes—compounds that modulate platelet activation
and promote vasoconstriction.7 Platelet adhesion and activation
at a site of injury, in concert with local vasoconstriction, provides
initial hemostasis for small-caliber vessels. Once hemostasis is
achieved by these mechanisms, the subsequent stabilization of
the platelet plug in a fibrin meshwork can proceed more effectively
than if bleeding continues. Initial hemostasis may be established
even if a deficiency of plasma coagulation proteins is present.
The platelet plug is insufficient, however, to provide long-term
hemostasis and delayed rebleeding occurs if it is not reinforced
by a stable fibrin clot during secondary hemostasis. Even after
overt bleeding (loss of red blood cells) is stopped by the stable
fibrin clot, leakage of plasma proteins from the microvasculature
continues. A hemostatic clot structure with a densely packed
core of platelets is required to form a tight vascular seal that
minimizes the leakage of plasma proteins at a site of injury.
It is becoming clear that, in addition to providing primary
hemostasis following an overt injury, platelets also play more
complex and subtle roles in maintaining vascular integrity. It
has long been known that platelets maintain endothelial integrity
in the microvasculature.9 A failure of this function is responsible
for petechiae resulting from thrombocytopenia. However, platelets
also directly prevent microvascular bleeding at sites of inflammation10 and angiogenesis11 by mechanisms that are independent
of fibrin generation.
12
Coagulation Proteins. Adequate levels and function of each of
a series of procoagulant proteins are required for hemostasis.
The coagulation proteins can be organized into several groups
based on their structural features.
The vitamin K–dependent factors include factors II (prothrombin), VII, IX, and X. These each have a structural domain
in which several glutamic acid residues are posttranslationally
modified to gamma carboxy-glutamic acid (Gla) residues by a
vitamin K–dependent carboxylase.13 The vitamin K cofactor is
oxidized from a quinone to an epoxide in the process. A vitamin
K epoxide reductase then cycles the vitamin K back to the quinone
form to allow carboxylation of additional glutamic acid residues.
The negatively charged Gla residues bind calcium ions. These
binding interactions hold the Gla-containing proteins in their
active conformation. The calcium-bound form of the Gla domain
is responsible for mediating binding of the coagulation factors
to phospholipid membranes. Lipids with negatively charged head
groups, particularly phosphatidylserine, are required for binding
and activity of the Gla-containing factors.
The carboxylation process is inhibited by the anticoagulant
warfarin, which competes with vitamin K for binding to the
reductase.14 This results in the production of undercarboxylated
forms of the vitamin K–dependent proteins, which are nonfunctional. The vitamin K–dependent procoagulants are zymogens
(inactive precursors) of serine proteases. Each is activated by
cleavage of at least one peptide bond. The activated form is
indicated by the letter “a.” Factors VIIa, IXa, and Xa each require
calcium ions, a suitable cell (phospholipid) membrane surface,
and a protein cofactor for their activity in hemostasis.
Factor IIa (thrombin) is a little different from the activated
forms of the other vitamin K–dependent factors. Its Gla domain
is released from the protease domain during activation. Thus,
it no longer binds directly to phospholipid membranes. It also
does not require a cofactor to cleave fibrinogen and initiate fibrin
assembly or to activate platelet receptors. IIa that escapes the
vicinity of a hemostatic plug can bind to a cofactor on endothelial
cell surfaces, that is, thrombomodulin.
15
After binding to thrombomodulin, IIa can no longer activate platelets or cleave fibrinogen.
Instead, it triggers an antithrombotic pathway by activating protein
C (PC) on the endothelial surface.
PC and protein S (PS) are also vitamin K–dependent factors.
They do not act as procoagulants but rather as antithrombotics
on endothelial surfaces.16 PC is the zymogen of a protease, while
PS has no enzymatic activity but serves as a cofactor for APC.
8
CHAPTER 8 Regulation of Hemostasis and Thrombosis 83
aX
https://t.me/medicina_free
The APC/PS complex cleaves and inactivates FVa and FVIIIa,
thus preventing propagation of thrombin generation on normal
healthy endothelium.
Factors V and VIII are large structurally related glycoproteins that act as cofactors. They have no enzymatic activity
of their own, but when activated by proteolytic cleavage dramatically enhance the proteolytic activity of factors Xa and IXa,
respectively.
Factor VIII circulates in a noncovalent complex with vWF,
which prolongs its half life in the circulation. The vWF-FVIII
complex binds to the platelet surface primarily via GPIb as vWF
mediates adhesion of platelets to collagen under high shear
conditions. Cleavage and activation of FVIII releases it from
vWF so that it can assemble into a complex with FIXa on the
platelet surface, where it activates FX.
FV circulates in the plasma and is packaged in the alpha granules of platelets during their development from megakaryocytes.17
It is released upon platelet activation in a partially activated form.
Both plasma and platelet-derived FV can be fully activated by
cleavage by FXa or IIa. The FVa then assembles into a complex
with FXa on the platelet surface, where it activates prothrombin
to IIa.
TF is also a cofactor but is structurally unrelated to any of
the other coagulation factors. Instead, it is related to one class
of cytokine receptors.18 This lineage emphasizes the close evolutionary and physiologic links between the coagulation system
and the other components of the host response to injury. Rather
than circulating in the plasma, as do the other coagulation factors,
TF is a transmembrane protein.19 TF serves as the cellular receptor
and cofactor for FVIIa. It is primarily expressed on cells outside
the vascular space under normal conditions, though monocytes
and endothelial cells can express TF in response to inflammatory
cytokines. The FVIIa/TF complex can activate both FIX and FX
and is the major initiator of hemostatic coagulation.
19
Another group of related proteins are the contact factors: factors
XI and XII and prekallekrein (PK) and high molecular weight
kininogen (HMK). These proteins share the feature of binding
to charged surfaces. The only one of this group that is needed
for normal hemostasis is factor XI.20 However, the other contact
factors may play a role in thrombosis in some settings. FXI is a
zymogen that can be activated to a protease by FXIIa but is likely
activated primarily by thrombin during the hemostatic process.
21,22
FXIa, in turn, activates FIX.
Fibrinogen provides the key structural component of the
hemostatic clot. Two small peptides, fibrinopeptides A and B,
are cleaved from fibrinogen by thrombin; the resulting fibrin
monomer polymerizes into a network of fibers. The fibrin polymer
is then stabilized further when it is crosslinked by activated
factor XIII. FXIIIa is a transglutaminase present in plasma and
platelets that is activated by thrombin coincident with fibrin
formation.
23
Thrombin plays a key role in activating procoagulant and
anticoagulant factors; it also has a key role in triggering formation
of fibrin. In addition, thrombin has cytokine-like activities that
bridge the transition between hemostasis, inflammatory/immune
responses, and wound healing. Thrombin is truly a multifunctional
molecule that impacts the host response to injury at many levels.
Even before the structure and function of the various factors
were defined, their interactions had been studied during plasma
clotting. In the 1960s, two groups proposed a “waterfall” or
“cascade” model of the interactions of the coagulation factors
leading to thrombin generation. These schemes were composed
of a sequential series of steps in which activation of one clotting
factor led to the activation of another, finally leading to a burst
of thrombin generation.
24,25
At that time, each clotting factor
was thought to exist as a proenzyme that was activated by
proteolysis. The existence of cofactors without enzymatic activity
was not recognized until later. The original models were subsequently modified as information about the coagulation factors
accumulated and eventually evolved into the “Y-shaped” scheme
shown in Fig. 8.1.
The cascade model shows distinct “intrinsic” and “extrinsic”
pathways that are initiated by FXIIa and FVIIa/TF, respectively.
The pathways converge on a common pathway at the level of
the FXa/FVa (prothrombinase) complex.
This scheme was not proposed as a literal model of the
hemostatic process in vivo; rather, it was derived from studies
of plasma clotting in a test tube and was intended to represent
the biochemical interactions of the procoagulant factors. In fact,
the coagulation cascade reflects very well the process of plasma
clotting, as in the PT and aPTT tests. However, the lack of any
other clear and predictive concept of hemostasis has meant that,
until recently, most physicians have also viewed the cascade as
EXTRINSIC PAT HWAY
Fig. 8.1 The extrinsic and intrinsic pathways in the modern
cascade model of coagulation. These two pathways are conceived
as each leading to formation of the factor Xa/Va complex, which
generates thrombin (IIa). Lipid/Ca indicates that the reaction
requires a phospholipid surface and calcium ions. These pathways
are assayed clinically using the prothrombin time (PT) and
activated partial thromboplastin time (aPTT), respectively. HK,
High-molecular-weight kininogen; PK, prekallikrein.
PT
VIIa
TF
Lipid/Ca
Xa
Va
Lipid/Ca
II IIa
Fibrinogen Fibrin
INTRINSIC PATHWAY
Xl
IXa
VIIIa
Lipid/Ca
aPTT
HK
XII
PK
I
IX
XX
84 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
a model of physiology and the PT and aPTT as reflecting the
risk of clinical bleeding.
The limitations of the coagulation cascade as a model of the
hemostatic process in vivo are highlighted by certain clinical
observations. Patients deficient in the initial components of the
intrinsic pathway—FXII, high molecular weight kininogen, or
PK—have a greatly prolonged aPTT but no bleeding tendency.
Patients deficient in FXI also have a prolonged aPTT but usually
have a mild to moderate bleeding tendency. Other components
of the intrinsic pathway clearly have a critical role in hemostasis
since patients deficient in factor VIII or IX have a serious bleeding
tendency even though the extrinsic pathway is intact. Similarly,
patients deficient in FVII also have a serious bleeding tendency
even though the intrinsic pathway is intact. Thus, although the
cascade model accurately reflects the protein interactions that
lead to plasma clotting and is an essential guide to interpretation
of PT and aPTT results, it is not an adequate model of hemostasis
in vivo.
Process of Hemostasis
Having all the right ingredients is not enough to ensure an effective
hemostatic process. Cellular interactions are crucial to directing
and controlling hemostasis. Of course, normal hemostasis is not
possible in the absence of platelets. In addition, TF is an integral
membrane protein; thus, its activity is normally associated with
cells, but platelets generally have little TF activity. Therefore
interactions between at least these two types of cells are necessary.
Because different cells express different levels of procoagulants
and anticoagulants as well as have different complements of
receptors, it is logical that simply representing the cells involved
in coagulation as phospholipid vesicles overlooks the active role
of cells in directing hemostasis. Hemostasis in vivo can be
conceptualized as occurring in a stepwise process, regulated by
cellular components.
Step 1: Initiation of Coagulation on TF-Bearing Cells. The
process of thrombin generation is initiated when TF-bearing
cells are exposed to blood at a site of injury. TF is a transmembrane
protein that acts as a receptor and cofactor for FVII. Once bound
to TF, zymogen FVII is rapidly converted to FVIIa through
mechanisms not yet completely understood but may involve
FXa or noncoagulation proteases. The resulting FVIIa/TF complex
catalyzes activation of FX and FIX. The factors Xa and IXa formed
on TF-bearing cells have very distinct and separate functions in
initiating blood coagulation.
cells interacts with its cofactor, FVa, to form prothrombinase
complexes and generate small amounts of thrombin on the TF
cells (Fig. 8.2). The small amounts of FVa required for prothrombinase assembly on TF-bearing cells are activated by FXa,28
by noncoagulation proteases produced by the cells,29 or are
released from platelets that adhere nearby. The activity of the
FXa formed by the FVIIa/TF complex is largely restricted to the
TF-bearing cell, because FXa that dissociates from the cell surface
is rapidly inhibited by tissue factor pathway inhibitor (TFPI) or
AT in the fluid phase.
In contrast to FXa, the FIXa activated by FVIIa/TF does not
act on the TF-bearing cell and does not play a significant role
26
27
The FXa formed on TF-bearing
X
VIIa
VIIa
IX
IXa
Fig. 8.2 The initiation step in a cell-based model of hemostasis.
Initiation occurs on the tissue factor (TF)-bearing cell as activated
FX combines with its cofactor, FVa, to activate small amounts
of thrombin.
Xa Xa
Tissue factor−bearing cell
II
IIa
Va
in the initiation phase of coagulation. FIXa can diffuse to adjacent
platelet surfaces because it is not inhibited by TFPI and is inhibited
much more slowly by AT than is FXa. FIXa can then bind to a
specific platelet surface receptor,30 interact with its cofactor, FVIIIa,
and begin to activate FX directly on the platelet surface.
The small amount of thrombin produced on the TF-bearing
cells is not sufficient to clot fibrinogen, but it is sufficient to
initiate events that amplify the initial procoagulant signal and
“prime” the clotting system for a subsequent burst of platelet
surface thrombin generation. This thrombin is responsible for
(1) activating platelets, (2) activating FV, (3) activating FVIII
and dissociating FVIII from vWF, and (4) activating FXI.
31,32
It is likely that most (extravascular) TF is bound to FVIIa
even in the absence of an injury and that low levels of FIXa,
FXa, and thrombin are produced on TF-bearing cells at all times.
However, this process is kept separated from key components
of hemostasis by an intact vessel wall. The very large components
of the coagulation process are platelets and FVIII bound to
multimeric vWF. These components normally only come in
contact with the extravascular compartment when an injury
disrupts the vessel wall. Platelets and FVIII-vWF then leave the
vascular space and adhere to collagen and other matrix components at the site of injury.
Step 2: Amplification of the Procoagulant Signal by Thrombin
Generated on the TF-Bearing Cell. Binding of platelets to
collagen or via vWF during primary hemostasis leads to partial
platelet activation. However, the coagulation process is most
effectively initiated when enough thrombin is generated on or
near the TF-bearing cells to trigger full activation of platelets.
Thrombin diffuses through the fluid phase, binds to its receptor
GPIb,33 and cleaves its proteolytically activated receptors.34 These
CHAPTER 8 Regulation of Hemostasis and Thrombosis 85
AMPLIFICATION
IX
https://t.me/medicina_free
X
VIIa Xa
TF
Tissue factor–
bearing cell
TF
IXa
IIa
Platelet
surface
Fig. 8.3 The amplification step in a cell-based model of hemostasis. The small amount of thrombin
generated on tissue factor (TF)-bearing cells amplifies the procoagulant response by diffusing to
the platelet surface, where it activates platelets via the protease activated receptor-1 (PAR-1),
activates FXI, and activates FVIII and releases it from its carrier molecule von Willbrand factor
(vWF).
Va
II
Xa
PAR-1
IIa
FVIII/vWF
FXI
FVIIIa
FXIa
two receptor types synergize in mediating platelet activation.
The small amounts of thrombin generated during the initiation
activated and have bound activated coagulation factors on their
surfaces.
step are also responsible for activation of coagulation factors XI
and VIII on the platelet surface in the amplification step, as
illustrated in Fig. 8.3.
Platelets not only plug the vascular defect at a site of injury
but also provide the specialized membrane surface on which
activation of many of the coagulation proteins takes place.
Unactivated platelets express a very low level of phosphatidylserine, the primary procoagulant phospholipid, on their surfaces.
Upon activation, phosphatidylserine is rapidly translocated from
the inner to the outer leaflet of the platelet plasma membrane.
It is then available to support binding and activity of the coagulation complexes.
35
Platelet secretion of granule contents occurs somewhat more
slowly after activation than does membrane surface changes.
Dense and alpha-granules within the platelet cytoplasm
contain numerous components that play a role in the coagulation process, such as partially activated FV, FVIII/vWF, FXIII,
fibrinogen, protease inhibitors, and platelet agonists (adenosine
diphosphate [ADP], epinephrine, and serotonin). Secretion of
these platelet agonists further enhances platelet activation. Once
platelets are activated, the cofactors Va and VIIIa are rapidly
localized on the platelet surface.36 FIXa formed by the FVIIa/
TF complex can diffuse through the fluid phase, bind to the
surface of activated platelets, and assemble into a complex with
FVIIIa. FXI activated by thrombin on the platelet surface
32,37
can
activate more FIX from the plasma to IXa. At the end of the
amplification phase, the platelets accumulated at the injury site are
Step 3: Propagation of Thrombin Generation on the Platelet
Surface. The multiple positive feedback mechanisms of the
amplification phase rapidly lead to a burst of thrombin generation
in the propagation phase, as illustrated in Fig. 8.4. The tenase
(FIXa/FVIIIa) complexes progressively activate FX from the
plasma to FXa on the platelet surface. FXa then associates with
FVa to support a burst of thrombin generation of sufficient
magnitude to produce a stable fibrin clot.
The large amount of thrombin generated on the platelet surface
is responsible for stabilizing the hemostatic clot in more ways
than just promoting fibrin polymerization. In fact, most of the
thrombin generated during the hemostatic process is produced
after the initial fibrin clot is formed. The platelet-produced
thrombin also stabilizes the clot by (1) activating FXIII,
38
(2)
activating the thrombin-activated fibrinolysis inhibitor (TAFI),39
(3) cleaving the platelet PAR-4 receptor,40 and (4) being incorporated into the structure of the clot. Activated FXIII covalently
crosslinks the fibrin strands and increases resistance to plasmin
degradation. TAFI also increases resistance to fibrinolysis by
cleaving off lysines from the fibrin strands that serve as sites for
fibrinolytic enzyme binding. Activation of platelet PAR-4 receptors
promotes clot contraction. The force generated by platelets is
considerable. Red blood cells trapped within the crosslinked
fibrin network are compressed into a tightly packed array that
contributes to the impermeable barrier needed for effective
hemostasis.
41
Clot contraction also pulls together the edges of
Соседние файлы в папке Библиотека им академика М.И. Перельмана