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IXa
X
IX
VIIIa
IXa
XIa
Activated platelet
Fig. 8.4 The propagation step in a cell-based model of hemostasis. The activated coagulation
factors bound to the platelet surface during the amplification phase progressively activate FX
and II from the plasma, resulting in a large burst of thrombin production.
II
Va
Xa
IIa
a wound and facilitates tissue repair. Excess thrombin produced
during the hemostatic process can remain bound within the
fibrin polymer and retains its proteolytic activity. Thus, it can
rapidly activate more platelets and clot more fibrinogen if the
hemostatic plug is disrupted and bleeding recommences.
The role of FXI in hemostasis has been a point of some
controversy since even severe FXI deficiency does not result in
a hemorrhagic tendency as severe as that in severe FVIII or IX
deficiency. This can be explained if FXI is viewed as a booster
of thrombin generation. FXI is not essential for platelet-surface
thrombin generation, as are FIX and FVIII. Rather, FXIa activates
additional FIXa on the platelet surface to supplement FIXa/FVIIIa
complex formation and enhance platelet surface FXa and
thrombin generation. Thus, its deficiency does not compromise
hemostasis to as great an extent as FIX or FVIII deficiency.
Our knowledge of the platelet contribution to thrombin
generation continues to evolve. There is evidence that there are
multiple types of activated platelets. Platelets with the highest
procoagulant activity are produced when they are stimulated
with both thrombin and collagen; these have been referred to
as COAT (collagen and thrombin stimulated) platelets.
42
These
platelets have enhanced thrombin-generating ability due to
enhanced binding of both tenase and prothrombinase compo-
43,44
nents.
The in vivo relevance of the COAT platelet phenomenon
is unclear, but it may be that the greatest procoagulant activity
is generated on platelets that have bound to collagen matrix and
also have been exposed to thrombin. When exposed collagen is
covered by a platelet/fibrin layer, additional platelets that accumulate are not activated to the COAT state—tending to damp
down the procoagulant signal once the area of the wound has
been walled off by a hemostatic clot.
45
Even though each phase of the cell-based model of hemostasis
has been depicted as a discrete step, these phases should be viewed
as an overlapping continuum of events. For example, thrombin
produced on the platelet surface early in the propagation phase
may initially cleave substrates on the platelet surface and continue
to amplify the procoagulant response in addition to leaving the
platelet and promoting fibrin assembly.
The cell-based model of hemostasis shows us that the extrinsic
and intrinsic pathways are not redundant. We can consider the
extrinsic pathway to consist of the FVIIa/TF complex, working
with the FXa/Va complex and the intrinsic pathway to consist
of FXIa working with the complexes of factors VIIIa/IXa and
factors Xa/Va. The extrinsic pathway operates on the TF-bearing
cell to produce small amounts of thrombin that initiate the
coagulation process and amplify the initial procoagulant signal.
By contrast, the intrinsic pathway operates on activated platelet
surfaces to produce the large burst of thrombin that leads to
formation and stabilization of the fibrin clot.
REGULATORY MECHANISMS TO
CONTROL COAGULATION
Although the inability to provide effective hemostasis is a
serious problem, the inability to limit coagulation to sites of
hemostasis is at least as great a problem. Therefore, multiple
biochemical and cellular regulatory mechanisms have evolved
to limit and localize coagulation reactions. Coagulation reactions do not cascade unimpeded into a torrent of thrombin
production but must instead overcome a series of regulatory
barriers.
Plasma Protease Inhibitors
Several circulating protease inhibitors can inactivate one or more
of the coagulation proteases. The coagulation proteases are relatively protected from inhibition while bound to a membrane
surface. Proteases that escape into the fluid phase are subject to
inhibition, however. Thus, the presence of inhibitors does not
prevent activation and activity of coagulation but tends to confine
the coagulation proteases to act on the cell surfaces on which
they were activated.
AT plays a particularly important role in regulating hemostasis.
AT is a serine protease inhibitor (serpin) that can inhibit most
of the procoagulant factors, including IIa, VIIa, IXa, Xa, and XIa.
The effectiveness of AT is increased by binding to heparinoids
on the endothelial surfaces as well as by exogenous heparins.
CHAPTER 8 Regulation of Hemostasis and Thrombosis 87
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IIa
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Both hereditary and acquired deficiencies of AT lead to a significant thrombotic tendency.
46
TFPI is also an important control mechanism. This molecule
is a multifunctional Kunitz-type inhibitor.47 One of its Kunitz
domains inhibits FXa. Once it has bound FXa, another Kunitz
domain can bind FVIIa in the FVIIa/TF complex. Thus, TFPI can
assist in localizing FXa to the cell surface on which it was activated
as well as limiting the activity of the TF pathway. Recently, it
was determined that PS (see following section of endothelial
antithrombotic mechanisms) serves as an important cofactor
for TFPI, enhancing its affinity for FXa dramatically.
48
Not only are the plasma protease inhibitors key players in
confining a clot to the proper location but they also impose a
threshold effect on activation of coagulation.49 Thus in the
presence of inhibitors, coagulation does not proceed unless
procoagulant factors are generated in sufficient amounts to
overcome the effects of inhibitors. If the triggering event is not
sufficiently strong, the system returns to baseline rather than
continuing through the coagulation process. Under pathologic
conditions, the trigger for clotting may be strong enough to
overwhelm the control mechanisms and lead to disseminated
intravascular coagulation or thrombosis.
Endothelial Antithrombotic Mechanisms
Once a fibrin/platelet clot is formed over an area of injury, the
clotting process must be terminated to avoid thrombotic occlusion
in adjacent normal areas of the vasculature. If the coagulation
mechanism is not controlled, clotting could extend throughout
the vascular tree after even a modest procoagulant stimulus.
Endothelial cells play a major role in confining the coagulation
reactions to a site of injury. Conversely, endothelial damage or
dysfunction can play a major role in promoting thrombosis.
Endothelial cells have several types of anticoagulant/antithrombotic
activities (Fig. 8.5). The PC/PS/thrombomodulin (TM) system
is activated in response to thrombin generation.50 Some of the
PS
PC
Fig. 8.5 Some antithrombotic mechanisms of the endothelial
cell surface. Endothelial cells express glycosaminoglycan (GAG)
molecules containing heparan sulfate to which thrombin and
antithrombin can bind. They also express TM and the endothelial
protein C receptor (EPCR) that localize components of the protein
C (PC)/protein S (PS) system to the endothelial surface. APC,
Activated protein C; TM, thrombomodulin.
Va iVa
APC
thrombin formed during hemostasis can diffuse away or be swept
downstream from a site of injury. When thrombin reaches an
intact endothelial cell, it binds to TM on its surface. The thrombin/
TM complex then activates PC, which is localized to the endothelial surface by binding to the endothelial PC receptor (EPCR).
The APC can then move into a complex with its cofactor, PS,
and inactivate any FVa or FVIIIa that has found its way to the
endothelial cell membrane. This prevents the generation of
additional thrombin in the intact vasculature. Endothelial cells
also localize anticoagulant protease inhibitors to their surfaces.
The protease inhibitor AT is bound to heparan sulfates expressed
on the endothelial surface where it can inactivate proteases near
the endothelium.51 TFPI can also be bound to heparan sulfate
or linked to the endothelial surface via a GPI anchor. Endothelial
cells also inhibit platelet activation by releasing the inhibitors
prostacyclin (PGI2) and nitric oxide (NO), as well as degrading
ADP by their membrane ecto-ADPase, CD39.
52
Fibrinolysis
Even as the fibrin clot is being formed in the body, the fibrinolytic
system is being initiated to disrupt it. The final effector of the
fibrinolytic system is plasmin, which cleaves fibrin into soluble
degradation products. Plasmin is produced from the inactive
precursor plasminogen by the action of two plasminogen activators: urokinase-type plasminogen activator (uPA) and tissue-type
plasminogen activator (tPA). The PAs, in turn, are regulated by
plasminogen activator inhibitors (PAIs). Plasminogen is found
at a much higher plasma concentration than the PAs. Therefore,
the availability of the two PAs in the plasma generally determines
the extent of plasmin formation. tPA release from endothelial
cells is provoked by thrombin and venous occlusion.53 tPA and
plasminogen both bind to the evolving fibrin polymer. Once
plasminogen is activated to plasmin, it cleaves fibrin at specific
lysine and arginine residues, resulting in dissolution of the fibrin
clot. The fibrinolytic system is crucial to removing an appropriate
hemostatic clot as wound healing occurs. It is also essential to
removing intravascular thrombi before significant tissue injury
can occur. For example, the pulmonary vasculature can release
large amounts of fibrinolytic enzymes to remove small thromboemboli that become lodged there.
Intravascular deposition of fibrin is also associated with the
development of atherosclerosis. Therefore, an effective fibrinolytic
system tends to protect against the chronic process of atherosclerotic vascular disease and the acute process of thrombosis.
Conversely, defects of fibrinolysis increase the risk of atherothrombotic disease. For example, elevated levels of PAI-1, an
inhibitor of fibrinolysis, are associated with an increased risk of
atherosclerosis and thrombosis,
54
as are decreased levels of
plasminogen.55 The effectiveness of hemostasis in vivo depends
not only on the procoagulant reactions but also on the fibrinolytic
process.
CLINICAL LABORATORY TESTING
The commonly used clinical coagulation tests do not reflect the
complexity of hemostasis in vivo. This does not mean that the
PT and aPTT are useless. Clinicians simply need to understand
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what these tests can and cannot tell us. These screening coagulation tests are abnormal when there is a deficiency of one or more
of the soluble coagulation factors. They do not predict the risk
of clinical bleeding. Two patients with identical aPTT values can
have drastically different risks of hemorrhage. All of the common
coagulation tests—including the PT, aPTT, thrombin clotting
time, fibrinogen levels, and coagulation factor levels—tell us
something about the plasma level of soluble factors required for
hemostasis. Their clinical implications must be evaluated by the
ordering physician. Just because the PT and aPTT are within
the normal range, it does not follow that the patient is at no risk
for bleeding. Conversely, a mild elevation in these clotting times
does not mean that the patient is at risk for bleeding after an
invasive procedure.
The assessment of platelet function has become an issue of
increasing importance in cardiac care. There is no doubt that
platelets contribute substantially to acute and chronic vascular
disorders. Individuals demonstrate substantial variability in
platelet responses to agonists. A number of pharmacologic agents
are now available to inhibit platelet function, and low platelet
reactivity is associated with a reduction in atherothrombotic
events in certain clinical settings. Conversely, low platelet
responsiveness is associated with an increased risk of bleeding
following cardiac surgery. Ideally, a test of platelet reactivity could
be used to determine when a patient had achieved an adequate
degree of platelet inhibition to optimally prevent future events,
and to determine when platelet inhibition had been reversed
sufficiently to minimize bleeding complications of an invasive
procedure. At present, none of the commercially available platelet
function testing systems has demonstrated sufficiently good
predictive accuracy to recommend their routine use for assessment
of platelet inhibition.
Many whole-blood coagulation tests are being presented as
a means of evaluating overall hemostatic status in selected clinical
settings. Although whole-blood tests have the advantage that
they can reflect the contributions of platelets to the hemostatic
process, they still do not reflect the contributions of TF-bearing
cells and local tissue conditions. In addition, they suffer from
the limitation that the reagents used to trigger initiation of
coagulation are often not physiologic (such as kaolin). These
tests of global hemostasis can be useful, especially when a rapid
turnaround time is essential. They can be helpful is assessing
whether a currently bleeding patient has a coagulopathy or an
anatomic cause of bleeding. In summary, any laboratory test
requires skilled interpretation and clinical correlation in evaluating
the true risk of bleeding or thrombosis.
bleeding include consumption of coagulation factors and platelets,
excessive fibrinolysis, hypothermia, and acidosis.
Consumption of Coagulation Components. Disseminated
intravascular coagulation (DIC) is the excessive consumption
of coagulation factors, platelets, and inhibitors that occurs
when the coagulation process is not properly localized to a site
of injury. However, clotting factors and platelets can also be
consumed during appropriate physiologic attempts at hemostasis.
In this case, it is appropriate to replace the depleted factors with
transfusion therapy.
DIC can be much more complicated to manage.56 The mainstay
of treatment is to treat the underlying disorder, such as sepsis.
In early or mild/compensated DIC, administration of low-dose
heparin may be considered to control the procoagulant response
to inflammation, infection, or malignancy. In more severe or
advanced DIC, replacement therapy may be necessary to attempt
to manage the bleeding tendency associated with depletion of
coagulation factors and platelets.
Excessive Fibrinolysis. The process of fibrinolysis is initiated
as the fibrin clot assembles. Fibrin serves as the framework to
which plasminogen binds and is activated to plasmin by tPA
and uPA. Even when formation of a fibrin clot does not succeed
at establishing hemostasis, a significant amount of fibrinolytic
activity may still be generated and thwart subsequent efforts at
hemostasis. Fibrinolytic inhibitors have proven to be useful in
some circumstances.
Hypothermia. Many patients become hypothermic during
medical illness or following surgical or accidental trauma.57
Hypothermia can directly interfere with the hemostatic process
by slowing the activity of the coagulation enzymes. Less well
recognized is the finding that platelet adhesion and aggregation
is impaired even in mild hypothermia.58 Thus, in hypothermic
coagulopathic patients, raising the core temperature can have a
beneficial effect on bleeding by improving both platelet function
and coagulation enzyme activity.
Acidosis. Acidosis can have an even more profound effect on
the coagulation process than does hypothermia, though the two
metabolic abnormalities often coexist. A drop in the pH from
7.4 to 7.2 reduces the activity of each of the coagulation proteases
by more than half.59 Thus acidosis should be considered as a
possible contributor to coagulopathic bleeding in both medical
and surgical patients.
WHAT CAN GO WRONG WITH HEMOSTASIS?
Hemorrhage
Many patients who develop hemorrhage do not have a preexisting
bleeding tendency. Bleeding following surgical or accidental
trauma, or during a medical illness, is often associated with the
development of an acquired coagulopathy. The hallmark of
coagulopathy is microvascular bleeding: oozing from cut surfaces
and minor sites of trauma, such as needle sticks. Microvascular
bleeding can lead to massive blood loss. Causes of coagulopathic
Thrombosis
Disruption of the normal regulatory functions of any of the
components of hemostasis can result in thrombosis. Generally,
thrombosis is a multifactorial problem: congenital and acquired
abnormalities in the antithrombotic activities of the vascular
endothelium can synergize with enhanced platelet reactivity and
alterations in procoagulant or anticoagulant levels to ultimately
produce thrombosis. The risk of thrombosis in any given individual
and any given time is a product of the individual’s accumulated
genetic, environmental, and lifestyle risk factors. Inflammation
CHAPTER 8 Regulation of Hemostasis and Thrombosis 89
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can trigger a number of responses that further predispose to
thrombosis.60 Coagulation and inflammatory responses interface
at the levels of the tissue factor pathway, the PC/PS system, and
the fibrinolytic system. Proinflammatory cytokines can affect
all of these coagulation mechanisms. Coagulation proteases,
anticoagulants, and fibrinolytic enzymes, in turn, can modulate
inflammation by specific cell receptors. For example, inflammatory
cytokines can promote an increase in tissue factor and a decrease
in thrombomodulin by the endothelium.61 Furthermore, activation
of coagulation is closely linked with the progression of athersclerotic vascular lesions. Progressively impaired vascular function
then further predisposes to thrombosis. Ultimately, rupture of an
unstable atherosclerotic plaque can expose procoagulant activity
and provoke an acute thrombotic event.62 Thus, management of
cardiovascular disease often involves preventing and managing
thrombosis and its consequences. Venous and arterial thrombosis
tend to have different mechanisms and risk factors; thus, they
are best managed by somewhat different strategies.
Venous Thrombosis. The major mechanism of venous throm-
bosis is related to inappropriate activation of the coagulation
reactions, often on inflamed endothelium. Stasis can play an
exacerbating role when activated factors are not rapidly diluted
in flowing blood. Abnormalities of coagulation factors and
increased levels of coagulation factors that potentially increase
thrombin generation are linked to venous thrombosis.
63,64
The
inherited hemostatic abnormalities most often associated with
venous thromboembolism are factor V Leiden and factor II
G20210A mutations, as well as deficiencies in AT, PC, and PS.
Acquired abnormalities also play a major role. Major clinical
risk factors for venous thromboembolism include malignancy,
myeloproliferative disorders, trauma, surgery (especially orthopedic surgery), immobilization or paralysis, and prior venous
thromboembolism. Minor risk factors include advanced age,
obesity, bed rest, the use of hormone-replacement therapy or
oral contraceptives, pregnancy and postpartum period, and
inflammatory bowel disease.
Venous thrombosis is extremely common among hospitalized
patients. While it is often asymptomatic, it is a significant cause
of morbidity and of mortality from pulmonary embolism. The
incidence of venous thrombosis can be reduced dramatically by
the appropriate use of thromboprophylaxis with anticoagulants
such as heparin and low-molecular-weight heparins.
65–67
turbulent flow. As atherosclerotic plaques develop, they not only
alter the nonthrombogenic nature of the endothelium but also
disrupt normal laminar blood flow and produce increased
turbulence. Although increased platelet reactivity can contribute
to arterial thrombosis, vascular alterations play a key role in
promoting platelet adhesion and activation.68 There is also
considerable evidence that TF-mediated activation of the coagulation system and thrombin generation can be important contributors to arterial thrombosis.69 Thrombin generation at a site of
plaque rupture can be the trigger for platelet activation and
adhesion.
70
The risk factors most closely linked to arterial thrombosis
are smoking, hypertension, dyslipidemia, and diabetes. Inherited
thrombophilia plays much less of a role in arterial than venous
thrombosis.71 Lifestyle changes can have a significant impact on
the risk of arterial thrombosis. However, the most effective
management is by therapies targeting platelet activation and
adhesion. The results of recent studies indicate that, in addition
to the efficacy of aspirin in reducing cardiac events in patients
suffering from acute coronary syndromes, more potent antiplatelet
and anticoagulant therapies are also valuable in high-risk patients.
What Happens After the Bleeding Stops?
Once hemostasis is completed, the process of wound healing
can begin. Many of the activities involved in wound healing are
influenced by thrombin. Thrombin plays a major role in platelet
activation and degranulation. Several key cytokines modulating
wound healing are released from activated platelets, including
transforming growth factor beta (TGF-β), and platelet-derived
growth factor (PDGF). Of course, the amount and rate of
thrombin generated during hemostasis influences the initial
structure of the fibrin clot, the framework on which cell migration
takes place. In addition, thrombin has chemotactic and mitogenic
activities for macrophages, fibroblasts, smooth muscle cells, and
endothelial cells. Thus, generation of the appropriate amount
of thrombin during the coagulation process may not only be
essential for effective hemostasis but may set the stage for effective
wound healing. Conversely, thrombin generation at sites of
vascular injury plays a role in the development of local inflammatory changes and progression of atherosclerotic lesions.
The full reference list for this chapter is available at
ExpertConsult.com.
Arterial Thrombosis. Arterial thrombosis is primarily related
to formation of platelet aggregates at sites of high shear and
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REFERENCES
1. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of
tissue factor in the normal vessel wall and in the atherosclerotic
plaque. Proc Natl Acad Sci USA. 1989;86(8):2839–2843.
2. Drake TA, Morrissey JH, Edgington TS. Selective cellular
expression of tissue factor in human tissues. Implications for
disorders of hemostasis and thrombosis. Am J Pathol.
1989;134(5):1087–1097.
3. Alberio L, Dale GL. Review article: platelet-collagen interactions:
membrane receptors and intracellular signalling pathways. Eur J
Clin Invest. 1999;29(12):1066–1076.
4. Perutelli P, Mori PG. The human platelet membrane
glycoprotein IIb/IIIa complex: a multi functional adhesion
receptor. Haematologica. 1992;77(2):162–168.
5. Kunicki TJ. The influence of platelet collagen receptor
polymorphisms in hemostasis and thrombotic disease.
Arterioscler Thromb Vasc Biol. 2002;22(1):14–20.
6. Bennett JS. Structure and function of the platelet integrin
alphaIIbbeta3. J Clin Invest. 2005;115(12):3363–3369.
7. FitzGerald GA. Mechanisms of platelet activation: thromboxane
A2 as an amplifying signal for other agonists. Am J Cardiol.
1991;68(7):11B–15B.
8. Welsh JD, Muthard RW, Stalker TJ, et al. A systems approach to
hemostasis: 4. How hemostatic thrombi limit the loss of
plasma-borne molecules from the microvasculature. Blood.
2016;127(12):1598–1605.
9. Kitchens CS, Weiss L. Ultrastructural changes of endothelium
associated with thrombocytopenia. Blood. 1975;46(4):567–578.
10. Goerge T, Ho-Tin-Noe B, Carbo C, et al. Inflammation induces
hemorrhage in thrombocytopenia. Blood.
2008;111(10):4958–4964.
11. Kisucka J, Butterfield CE, Duda DG, et al. Platelets and platelet
adhesion support angiogeneasis while preventing excessive
hemorrhage. Proc Natl Acad Sci USA. 2006;103(4):855–860.
12. Hoffman M, Monroe DM. Inflammation does not predispose to
bleeding in hemophilia. J Thromb Haemost. 2010;8(11):
2583–2585.
13. Stafford DW. The vitamin K cycle. J Thromb Haemost.
2005;3(8):1873–1878.
14. Wallin R, Hutson SM. Warfarin and the vitamin K-dependent
gamma-carboxylation system. Trends Mol Med. 2004;10(7):
299–302.
15. Dittman W, Nelson S. Thrombomodulin. In: High KA, Roberts
HR, eds. Molecular Basis of Thrombosis and Hemostasis. New
York: Marcel Dekker; 1995:425–445.
16. Dahlback B. Progress in the understanding of the protein C
anticoagulant pathway. Int J Hematol. 2004;79(2):109–116.
17. Gould WR, Simioni P, Silveira JR, et al. Megakaryocytes
endocytose and subsequently modify human factor V in vivo to
form the entire pool of a unique platelet-derived cofactor. J
Thromb Haemost. 2005;3(3):450–456.
18. Harlos K, Martin DM, O’Brien DP, et al. Crystal structure of the
extracellular region of human tissue factor. Nature.
1994;370(6491):662–666.
19. Nemerson Y. The tissue factor pathway of blood coagulation.
Semin Hematol. 1992;29(3):170–176.
20. Fujikawa K, Chung DW, Factor XI. In: High KA, Roberts HR,
eds. Molecular Basis of Thrombosis and Hemostasis. New York:
Marcel Dekker; 1995:257–268.
21. Gailani D, Broze GJ Jr, Factor XI. Activation in a revised model
of blood coagulation. Science. 1991;253:909–912.
22. Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin
activates factor XI on activated platelets in the absence of factor
XII. Arterioscler Thromb Vasc Biol. 1999;19(1):170–177.
23. Lai T-S, Greenberg C, Factor XIII. In: High KA, Roberts HR, eds.
Molecular Basis of Thrombosis and Hemostasis. New York: Marcel
Dekker; 1995:287–308.
24. MacFarlane RG. An enzyme cascade in the blood clotting
mechanism, and its function as a biological amplifier. Nature.
1964;202:498–499.
25. Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood
clotting. Science. 1964;145:1310–1312.
26. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis.
Thromb Haemost. 2001;85(6):958–965.
27. Hoffman M, Monroe DM, Oliver JA, Roberts HR. Factors IXa
and Xa play distinct roles in tissue factor-dependent initiation of
coagulation. Blood. 1995;86(5):1794–1801.
28. Monkovic DD, Tracy PB. Activation of human factor V by factor
Xa and thrombin. Biochemistry. 1990;29:1118–1128.
29. Allen DH, Tracy PB. Human coagulation factor V is activated to
the functional cofactor by elastase and cathepsin G expressed at
the monocyte surface. J Biol Chem. 1995;270(3):1408–1415.
30. Ahmad SS, Rawala-Sheikh R, Ashby B, Walsh PN. Platelet
receptor-mediated factor X activation by factor IX. High-affinity
factor IXa receptors induced by factor VIII are deficient on
platelets in Scott syndrome. J Clin Invest. 1998;84:824–828.
31. Monroe DM, Hoffman M, Roberts HR. Transmission of a
procoagulant signal from tissue factor-bearing cell to platelets.
Blood Coagul Fibrinolysis. 1996;7(4):459–464.
32. Oliver J, Monroe D, Roberts H, Hoffman M. Thrombin activates
factor XI on activated platelets in the absence of factor XII.
Arterioscler Thromb Vasc Biol. 1999;19(2):170–177.
33. Ramakrishnan V, DeGuzman F, Bao M, et al. A thrombin
receptor function for platelet glycoprotein Ib-IX unmasked by
cleavage of glycoprotein V. Proc Natl Acad Sci USA.
2001;98(4):1823–1828.
34. Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning
of a functional thrombin receptor reveals a novel proteolytic
mechanism of receptor activation. Cell. 1991;64(6):1057–1068.
35. Bevers EM, Rosing J, Zwaal RF. Development of procoagulant
binding sites on the platelet surface. Adv Exp Med Biol.
1985;192:359–371.
36. Monroe DM, Roberts HR, Hoffman M. Platelet procoagulant
complex assembly in a tissue factor-initiated system. Br J
Haematol. 1994;88:364–371.
37. Baglia FA, Walsh PN. Prothrombin is a cofactor for the binding
of factor XI to the platelet surface and for platelet-mediated
factor XI activation by thrombin. Biochemistry. 1998;37:
2271–2281.
38. Lorand L. Factor XIII: structure, activation, and interactions
with fibrinogen and fibrin. Ann N Y Acad Sci. 2001;936:291–311.
39. Bajzar L, Manuel R, Nesheim ME. Purification and
characterization of TAFI, a thrombin-activable fibrinolysis
inhibitor. J Biol Chem. 1995;270(24):14477–14484.
40. Ofosu FA. Protease activated receptors 1 and 4 govern the
responses of human platelets to thrombin. Transfus Apher Sci.
2003;28(3):265–268.
41. Cines DB, Lebedeva T, Nagaswami C, et al. Clot contraction:
compression of erythrocytes into tightly packed polyhedra and
redistribution of platelets and fibrin. Blood. 2014;123(10):
1596–1603.
42. Alberio LJ, Clemetson KJ. All platelets are not equal: COAT
platelets. Curr Hematol Rep. 2004;3(5):338–343.
89.e2 PART II Scientific Foundation of Cardiac Intensive Care
https://t.me/medicina_free
43. Dale GL, Friese P, Batar P, et al. Stimulated platelets use
serotonin to enhance their retention of procoagulant proteins on
the cell surface. Nature. 2002;415(6868):175–179.
44. Kempton CL, Hoffman M, Roberts HR, Monroe DM. Platelet
Heterogeneity. Variation in Coagulation Complexes on Platelet
Subpopulations. Arterioscler Thromb Vasc Biol. 2005;25:861–866.
45. Mazepa M, Hoffman M, Monroe D. Superactivated platelets:
thrombus regulators, thrombin generators, and potential clinical
targets. Arterioscler Thromb Vasc Biol. 2013;33(8):1747–1752.
46. Maclean PS, Tait RC. Hereditary and acquired antithrombin
deficiency: epidemiology, pathogenesis and treatment options.
Drugs. 2007;67(10):1429–1440.
47. Broze GJ Jr. The rediscovery and isolation of TFPI. J Thromb
Haemost. 2003;1(8):1671–1675.
48. Hackeng TM, Rosing J. Protein S as cofactor for TFPI.
Arterioscler Thromb Vasc Biol. 2009;29(12):2015–2020.
49. Jesty J, Beltrami E, Willems G. Mathematical analysis of a
proteolytic positive-feedback loop: Dependence of lag time and
enzyme yields on the initial conditions and kinetic parameters.
Biochemistry. 1993;32:6266–6274.
50. Oliver JA, Monroe DM, Church FC, Roberts HR, Hoffman M.
Activated protein C cleaves factor Va more efficiently on
endothelium than on platelet surfaces. Blood. 2002;100(2):
539–546.
51. de Agostini A, Watkins S, Slayter H, Youssoufian H, Rosenberg R.
Localization of the anticoagulantly active heparan sulphate
proteoglycans in vascular endothelium: antithrombin binding on
cultured endothelial cells and perfused rat aorta. J Cell Biol.
1990;111:1293–1304.
52. Marcus AJ, Broekman MJ, Drosopoulos JHF, et al. The
endothelial cell ecto-ADPase responsible for inhibition of
platelet function is CD39. J Clin Invest. 1997;99(6):1351–1360.
53. Szymanski LM, Pate RR, Durstine JL. Effects of maximal exercise
and venous occlusion on fibrinolytic activity in physically active
and inactive men. J Appl Physiol. 1994;77(5):2305–2310.
54. Nieswandt B, Brakebusch C, Bergmeier W, et al. Glycoprotein VI
but not {{alpha}}2{beta}1 integrin is essential for platelet
interaction with collagen. EMBO J. 2001;20(9):2120–2130.
55. Xiao Q, Danton MJ, Witte DP, et al. Plasminogen deficiency
accelerates vessel wall disease in mice predisposed to
atherosclerosis. Proc Natl Acad Sci USA. 1997;94(19):
10335–10340.
56. Franchini M. Pathophysiology, diagnosis and treatment of
disseminated intravascular coagulation: an update. Clin Lab.
2005;51(11–12):633–639.
57. Eddy VA, Morris JA Jr, Cullinane DC. Hypothermia,
coagulopathy, and acidosis. Surg Clin North Am.
2000;80(3):845–854.
58. Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A
systematic evaluation of the effect of temperature on coagulation
enzyme activity and platelet function. J Trauma.
2004;56(6):1221–1228.
59. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. The effect
of temperature and pH on the activity of factor VIIa:
implications for the efficacy of high-dose factor VIIa in
hypothermic and acidotic patients. J Trauma. 2003;55(5):
886–891.
60. Levi M, van der Poll T. Two-way interactions between
inflammation and coagulation. Trends Cardiovasc Med.
2005;15(7):254–259.
61. Meerarani P, Moreno PR, Cimmino G, Badimon JJ.
Atherothrombosis: role of tissue factor; link between diabetes,
obesity and inflammation. Indian J Exp Biol. 2007;45(1):
103–110.
62. Hellings WE, Peeters W, Moll FL, Pasterkamp G. From
vulnerable plaque to vulnerable patient: the search for
biomarkers of plaque destabilization. Trends Cardiovasc Med.
2007;17(5):162–171.
63. Bertina RM. Elevated clotting factor levels and venous
thrombosis. Pathophysiol Haemost Thromb. 2003;33(5–6):
395–400.
64. Lensen R, Rosendaal F, Vandenbroucke J, Bertina R. Factor V
Leiden: the venous thrombotic risk in thrombophilic families. Br
J Haematol. 2000;110(4):939–945.
65. Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA.
Meta-analysis: anticoagulant prophylaxis to prevent symptomatic
venous thromboembolism in hospitalized medical patients. Ann
Intern Med. 2007;146(4):278–288.
66. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent
venous thromboembolism among hospitalized patients. N Engl J
Med. 2005;352(10):969–977.
67. Goldhaber SZ. Venous thromboembolism: how to prevent a
tr agedy. Hosp Pract (Off Ed). 1988;23(10):164, 169–170, 173–164.
68. Ruggeri ZM. Role of von Willebrand factor in platelet thrombus
formation. Ann Med. 2000;32(suppl 1):2–9.
69. Heras M, Chesebro JH, Penny WJ, et al. Effects of thrombin
inhibition on the development of acute platelet-thrombus
deposition during angioplasty in pigs. Heparin versus
recombinant hirudin, a specific thrombin inhibitor. Circulation.
1989;79(3):657–665.
70. van Zanten GH, de Graaf S, Slootweg PJ, et al. Increased platelet
deposition on atherosclerotic coronary arteries. J Clin Invest.
1994;93(2):615–632.
71. de Moerloose P, Boehlen F. Inherited thrombophilia in arterial
disease: a selective review. Semin Hematol. 2007;44(2):106–113.
SECTION 1 Acute Myocardial Infarction
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Diagnosis of Acute Myocardial Infarction
OUTLINE
History, 91
Definition of Myocardial Infarction, 92
Biochemical Markers of Acute Myocardial Infarction, 92
Troponin, 93
Diagnosis, 93
Prognosis, 94
Risk Stratification, 94
Creatine Kinase MB, 94
Myoglobin, 94
Adjunctive Biomarkers, 94
Novel Cardiac Markers, 95
Clinical Evaluation, 95
Reinfarction, 98
Conclusion, 98
9
Matthew J. Chung, David L. Brown
Physical Examination, 96
Electrocardiogram, 96
Bundle Branch Block Patterns and Acute Myocardial
Infarction, 97
Imaging Techniques, 98
Myocardial infarction (MI) describes the process of myocardial
cell death caused by ischemia or the imbalance between myocardial
oxygen supply via the coronary arteries and demand. In the
United States each year, an estimated 1.1 million people experience
an acute MI or die from coronary heart disease.1 In 2016, it was
estimated that approximately every 34 seconds one American
would have a coronary event and about every 1 minute 24 seconds
an individual would die from a coronary event.1 According to
the most recent World Health Organization report in 2015,
coronary heart disease remains the leading cause of death
worldwide. Hence the early recognition and diagnosis of acute
MI is vital for the institution of therapy to limit myocardial
damage, preserve cardiac function, and reduce mortality.
Acute coronary syndrome (ACS) refers to the constellation
of clinical signs and symptoms caused by worsening myocardial
ischemia. In the absence of myocardial damage, assessed by
measuring cardiac biomarker levels, patients can be classified as
having unstable angina. When myocardial damage is present,
patients with ACS can be grouped into two major categories of
acute MI: (1) patients with new ST segment elevation on the
electrocardiogram (ECG) that is diagnostic of acute ST segment
elevation myocardial infarction (STEMI), and (2) patients with
non–ST segment elevation myocardial infarction (NSTEMI) who
have elevated cardiac biomarkers in an appropriate clinical setting,
with or without ischemic ECG changes.
Clinical trials have established the benefit of early reperfusion
therapy in patients with STEMI and an early invasive strategy
in patients with high-risk NSTEMI; thus a rapid and accurate
assessment of patients with suspected acute MI is essential for
optimal management.
modalities for the evaluation of patients with suspected
acute MI.
2,3
This chapter describes the diagnostic
2
HISTORY
There have been considerable advances in the detection of
myocardial injury and necrosis in the last several decades; as a
result, the definition of MI has evolved over time. Beginning in
the 1950s, the World Health Organization used epidemiologic
data to define acute MI as the presence of at least two of the
following three criteria: (1) clinical symptoms suggestive of
myocardial ischemia, (2) ECG abnormalities, or (3) elevation in
serum markers indicative of myocardial necrosis.4 Subsequently,
the development of more sensitive and specific biomarkers and
precise imaging techniques to detect subtle myocardial necrosis
has led to further refinement of the diagnosis of MI. In 1999,
91
CHAPTER 9 Diagnosis of Acute Myocardial Infarction 91.e1
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Keywords
myocardial infarction
cardiac biomarkers
92 PART III Coronary Artery Disease
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a consensus conference convened by the European Society of
Cardiology and the American College of Cardiology Foundation
published the first universal definition of MI. With ongoing
advances in the diagnosis and management of MI, this definition
was updated in 2007 by a Global Task Force assembled from
the European Society of Cardiology, the American College of
Cardiology Foundation, the American Heart Association, and
the World Heart Federation. Most recently, in 2012, the same
groups assembled and published the third universal definition of
MI with the goals of standardizing cardiac biomarker detection,
the use of cardiac imaging in the evaluation of a patient with
MI, and the classification of different types of MIs.
5
DEFINITION OF MYOCARDIAL INFARCTION
MI is defined as myocardial necrosis caused by prolonged
myocardial ischemia. The diagnosis of acute MI requires the rise
and/or fall of cardiac biomarkers (preferably troponin) with at
least one value exceeding the 99th percentile of a normal reference
population (the upper reference limit) and at least one of the
following: symptoms of ischemia, ECG changes indicative of
active ischemia (new ST segment–T wave changes or new left
bundle branch block [LBBB]) or infarction (new pathologic Q
waves), identification of an intracoronary thrombus by angiography or autopsy, imaging evidence of a new regional wall motion
abnormality, or new loss of viable myocardium.5 The type of
acute MI can be classified further depending on the etiology of
the infarct (Table 9.1). Prior MI is defined as pathologic Q waves,
regardless of symptoms, in the absence of nonischemic causes,
pathologic findings of a healed or healing MI, or imaging evidence
of a region of nonviable myocardium.
BIOCHEMICAL MARKERS OF ACUTE
MYOCARDIAL INFARCTION
The ideal biochemical marker to detect an acute MI should be
present in high concentration in the myocardium, absent in
noncardiac tissue, released rapidly in a linear fashion after
myocardial necrosis, and should remain present in the serum
long enough to be easily detectable by an inexpensive and widely
available assay. Table 9.2 summarizes serum cardiac markers.
Cardiac biomarkers are an essential component of the criteria
used to establish the diagnosis of acute MI. Cardiac troponins
(I or T) have become the preferred biomarkers for the detection
of myocardial necrosis; their use is a class I indication in the
diagnosis of MI.
5–7
The improved sensitivity and tissue specificity
of cardiac troponins compared with creatine kinase MB (CK-MB)
and other conventional cardiac biochemical markers of acute
MI has been well established.
7,8
Troponins are not only useful
for diagnostic implications but they also impart prognostic
information and can assist in the risk stratification of patients
presenting with suspected ACS.
In addition to the established biomarkers of myocardial
necrosis, B-type natriuretic peptide (BNP) and C-reactive protein
(CRP) are pathologically diverse biomarkers that could potentially
enhance risk stratification in ACS. Additionally, several novel
markers of myocardial ischemia and their usefulness during acute
MI are currently being evaluated in clinical studies. However,
to date, measurement of more than one specific biomarker of
myocardial necrosis is unnecessary and not recommended for
establishing the diagnosis of MI.9 Furthermore, certain biomarkers
should no longer be used in the evaluation of acute MI because
of poor specificity secondary to their wide tissue distribution,
including aspartate aminotransferase, total lactate dehydrogenase,
and lactate dehydrogenase isoenzymes.
10
TABLE 9.1 Universal Classification of
Myocardial Infarction (MI)
Type Description
1 Spontaneous MI resulting from an atherosclerotic plaque rupture,
ulceration, fissuring, erosion, or dissection with resulting
intraluminal thrombus
2 MI associated with ischemia due to an imbalance in myocardial
oxygen supply and demand, such as in coronary endothelial
dysfunction, coronary artery spasm, coronary embolism,
anemia, arrhythmias, hypertension, or hypotension
3 MI resulting in cardiac death, with symptoms suggestive of
myocardial ischemia, accompanied by new ischemic
electrocardiogram changes, but death occurring before blood
samples could be obtained, or at a time before the appearance
of cardiac biomarkers in the blood
4a MI associated with percutaneous coronary intervention
4b MI associated with stent thrombosis as documented by
angiography or autopsy
5 MI associated with coronary artery bypass graft surgery
Modified and adapted from Thygesen K, Alpert JS, Jaffe AS, et al.
Third universal definition of myocardial infarction. J Am Coll Cardiol.
2012;60:1581–1598.
TABLE 9.2 Biochemical Markers of Myocardial Necrosis
Marker Initial Appearance (h) Mean Time to Peak Return to Basal Sampling Schedule
Myoglobin 1–4
CK–MB (tissue isoform) 2–6 18 h 48–72 h Initially, then every 3–6 h
Cardiac troponin I 3–6 24 h 7–10 days Initially, then every 3–6 h
Cardiac troponin T 3–6 12–48 h 10–14 days Initially, then every 3–6 h
CK 3–12 24 h 72–96 h Initially, then every 8 h
Lactate dehydrogenase (LDH) 10 48–72 h 10–14 days Once at least 24 h after chest pain
Modified from Adams J, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury: is MB creatine kinase the choice for the 1990’s?
Circulation. 1993;88:750–763.
CK-MB, MB isoenzyme of creatine kinase (CK).
6–7 h 12–24 h Initially, then every 1–2 h
x Upper limit of normal
7
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CHAPTER 9 Diagnosis of Acute Myocardial Infarction 93
Detectable increases in cardiac biomarkers are indicative of
myocardial injury. However, cardiac biomarker elevations are
not synonymous with acute MI. Many disease states, such as
sepsis, congestive heart failure, pulmonary embolism, myocarditis,
intracranial hemorrhage, stroke, and renal failure can be associated
with an increase in cardiac biomarkers. These elevations arise
from mechanisms other than thrombotic coronary artery occlusion and require treatment of the underlying cause rather than
the administration of antithrombotic and antiplatelet agents.
11,12
Acute MI should be diagnosed when cardiac biomarkers are
abnormal and the clinical setting is consistent with myocardial
ischemia.
Troponin
Cardiac troponins are regulatory proteins that control the
calcium-mediated interaction of actin and myosin, which results
in contraction and relaxation in striated muscle. The troponin
complex comprises three subunits: troponin C, which binds
calcium; troponin I, which inhibits actin-myosin interactions;
and troponin T, which attaches the troponin complex by binding
to tropomyosin and facilitates contraction. Troponin C is
expressed by cells in cardiac and skeletal muscle; in contrast, the
amino acid sequences of troponins I and T are unique to cardiac
muscle. This difference has allowed for the development of rapid,
quantitative assays to detect elevations of cardiac troponins in
the serum. Troponin is the preferred biomarker for use in the
diagnosis of acute MI because of superior tissue specificity and
sensitivity for MI and its usefulness as a prognostic indicator.
Diagnosis. Troponin is released early in the course of acute
MI. An increased concentration of cardiac troponin is defined
as exceeding the 99th percentile of a normal reference population.
Troponin exceeding this limit on at least one occasion in the
setting of clinical myocardial ischemia is indicative of an acute
MI.5 Elevated troponin can be detected within 3 to 4 hours after
the onset of myocardial injury.12 Serum levels can remain increased
for 7 to 10 days for troponin I and 10 to 14 days for troponin
T (Fig. 9.1).
13
The initial release of troponin is from the cellular cytosol,
whereas the persistent elevation is a result of the slower dispersion
of troponin from degrading cardiac myofilaments.14 As a result
of these kinetics, the sensitivity of troponin increases with time.
At 60 minutes after the onset of acute MI, the sensitivity is
approximately 90%, but maximal sensitivity of troponin (≈99%)
is not achieved until 6 or more hours after the initiation of
myocardial necrosis.12 Blood samples for the measurement of
troponin levels are recommended to be drawn at presentation
and 6 to 9 hours later to optimize the clinical sensitivity for
ruling in acute MI and the specificity for ruling out acute MI.
The sensitivity and specificity of cardiac troponins is approximately 95% and 90%, respectively, with serial testing up to 12
hours after arrival at the hospital.15 As a result of its high tissue
specificity, cardiac troponin is associated with fewer false-positive
results in the setting of concomitant skeletal muscle injury
compared with CK-MB. This inherent characteristic of troponin
is useful in the assessment of myocardial injury in patients with
chronic muscle diseases, perioperative MIs, and after electrical
Fig. 9.1 Time course of biochemical marker levels during acute
myocardial infarction. The relative timing and extent of the
increase above normal values of the commonly used serum
markers during acute myocardial infarction are shown. CK,
Creatine kinase; CK-MB, creatine kinase MB isoenzyme; LDH,
lactate dehydrogenase.
cardioversion or blunt cardiac trauma.
note that although cardiac troponin is highly tissue specific, its
elevation does not indicate the mechanism of myocardial injury;
if elevated troponins are found in the absence of myocardial
ischemia, an evaluation for alternative etiologies of myocardial
injury should be pursued.
high-sensitivity cardiac troponin assays, which are able to detect
very low concentrations of cardiac troponins due to changes in
how the assays are performed. High-sensitivity troponins are
often abnormal earlier than conventional troponins in patients
with acute MI. Because of this characteristic, high-sensitivity
troponins can be used to safely and accurately rule out patients
with suspected ACS more quickly than when using conventional
troponins.20 However, uncertainties about appropriate cut-off
values for high-sensitivity troponins, difficulty in distinguishing
between acute and chronic causes of high-sensitivity troponin
elevations, and lack of clarity regarding the optimal duration of
the rule-out period for acute MI have prevented the mainstream
use of this assay in current practice.
not reliably permit the very early (initial 1 to 2 hours) detection
of myocardial necrosis, the diagnosis of acute MI in patients
presenting within 6 hours of symptom onset must be based
on the clinical scenario, ECG findings, and adjunctive imaging
7
techniques. In the case of STEMI, reperfusion therapy should not
be delayed by waiting for biomarkers confirmatory of myocardial
injury.
NSTEMI but also serve to direct treatment by identifying patients
who would benefit from an early invasive management strategy.22
In the Treat Angina with Aggrastat and Determine Cost of Therapy
with an Invasive or Conservative Strategy–Thrombolysis in
Myocardial Infarction 18 (TACTICS–TIMI 18) study, patients
6
5
4
3
2
1
02040
60 80
Hours from onset of infarction
Myoglobin
CK-MB
Troponin I
To tal CK
LDH
100120 14
16–19
It is important to
More recently, there has been the ongoing development of
21
Thus, with the use of conventional troponin assays that do
Elevated troponins are not only vital to the diagnosis of
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