Page 2067 - Hematology_ Basic Principles and Practice ( PDFDrive )

1836 Part XII Hemostasis and Thrombosis

tissue factor transfer occurs. By binding to adhesion molecules Emerging Role of the Contact Pathway
expressed on activated endothelial cells or to P-selectin on activated
platelets, these tissue factor–bearing cells or microparticles can initiate The contact pathway has emerged as an important player in thrombo-
or augment coagulation. This phenomenon likely explains how sis. It has long been recognized that the contact pathway is dispensable
venous thrombi develop in the absence of obvious vessel wall injury. for hemostasis because of the lack of a bleeding diathesis in patients
Tissue factor is an integral membrane protein that serves as a with hereditary deficiency of factor XII, prekallikrein, or high-molecular-
receptor for factor VIIa. Blood contains trace amounts of factor VIIa, weight kininogen and the mild bleeding diathesis with factor XI defi-
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which has negligible activity in the absence of tissue factor. Although ciency relative to deficiencies of factor VIII or factor IX. However, until
tissue factor is present on cell surfaces, it is proposed to exist in an recently, the role of the contact pathway remained elusive. The pathway
was ignored for several decades because its activators were mainly
encrypted, inactive form. The decryption step is thought to occur by nonphysiologic substances such as kaolin or ellagic acid, compounded
a disulfide bond rearrangement catalyzed by protein-disulfide isom- by the observation that thrombin could activate factor XI, providing a
erase and exposure of phosphatidylserine on the outer membrane potential physiologic bypass for the contact system as the activator of
surface. Factor VIIa binds tissue factor in a calcium-dependent intrinsic tenase.
fashion to form the extrinsic tenase complex, which is a potent activa- The renaissance in our understanding of the important contribution
tor of factors IX and X. Once activated, factor IXa and factor Xa of the contact pathway to thrombus stabilization and propagation
serve as the enzyme components of intrinsic tenase and prothrombi- occurred as a result of the identification of new physiologic activators,
nase, respectively. Because sufficient levels of factor Xa and thrombin the attenuated thrombosis after venous or arterial injury observed in
are formed in response to exposure of tissue factor, the extrinsic tenase mice deficient in factor XII or XI, and the development of contact
pathway–specific inhibitors. Reports that factor XI-deficient mice were
complex is considered the essential mediator of the initiation phase. protected from arterial injury–induced thrombosis to the same extent
as factor IX-deficient mice, but did not experience bleeding, provide a
clear demarcation between hemostasis and thrombosis. The role of the
Intrinsic Tenase contact pathway in thrombosis gained credibility with the observation
that mice lacking factor XII were also resistant to clot formation at sites
Factor IXa binds to factor VIIIa on anionic platelet or cell surfaces of vascular injury. However, the physiologic mechanism for activation
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to form the intrinsic tenase complex. Factor VIII circulates in blood of the pathway remained unclear until studies showed that nuclear
in complex with vWF. Thrombin cleaves factor VIII and releases it material released from neutrophils in the form of neutrophil extra-
from vWF, converting it to its activated form. Activated platelets cellular traps, nucleic acids, and inorganic polyphosphates released
from activated platelets or microorganisms, activated coagulation in a
express binding sites for factor VIIIa. Once bound, factor VIIIa binds contact pathway–dependent fashion. With a valid association between
factor IXa in a calcium-dependent fashion to form the intrinsic tenase the contact pathway and physiologic activators, investigation into the
complex, which then activates factor X. The loss in catalytic efficiency role of the contact pathway in thrombosis exploded.
of intrinsic tenase that occurs with a deficiency of factors VIII or IX Renewed interest in the contact pathway has spurred investigation of
in hemophilia A and B, respectively, highlights their importance. factors XI and XII as targets for new antithrombotic drugs. Agents tar-
Absence of the membrane or factor VIIIa almost completely abolishes geting factors XI and XII include biological inhibitors, antibodies, small
enzymatic activity, and the catalytic efficiency of the complete molecule inhibitors, and aptamers. Another approach is to reduce factor
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complex is 10 -fold greater than that of factor IXa alone. Because levels by inhibiting protein expression through the use of antisense
intrinsic tenase activates factor X at a rate 50- to 100-fold faster than oligonucleotides (ASO). This approach has been successfully applied
to factor XI, where administration of an ASO reduced postoperative
extrinsic tenase, it plays a critical role in the amplification of factor thrombosis in patients undergoing total knee arthroplasty, without an
Xa and subsequent thrombin generation. Thus intrinsic tenase is increase in bleeding. Similar interest in targeting the contact pathway is
crucial to the propagation phase of coagulation. directed at device-related thrombosis. Thrombosis is a major cause of
failure of blood-contacting medical devices, a problem that can lead to
life-threatening complications including pulmonary embolism, coronary
Contact Pathway occlusion, and stroke. and activation of the contact pathway by the
artificial surface is thought to be the primary cause. Therefore the
The contact pathway is so named because initial identification of its contact pathway has emerged as an attractive target for development
constituents (factors XII, XI, IX, and kallikrein), required contact of agents that reduce thrombosis with little impact on hemostasis.
with artificial agents such as ellagic acid or silica for activation. For
this reason, the contact pathway lost prominence when the physiologic
tissue factor pathway was identified. Current thinking is that tissue
factor exposure represents the sole pathway for activation of coagula- In addition to its role in device-related thrombosis, the contact
tion and thus the contact system is unimportant for hemostasis pathway may also contribute to the stability of arterial and venous
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because patients deficient in factor XII, prekallikrein, and high- thrombi. NETs, and DNA and RNA released from damaged cells
molecular-weight kininogen do not have bleeding problems (see in atherosclerotic plaques, activate factor XII, and mice given DNA-
Chapter 126). Although patients with severe deficiency of factor XI or RNA-degrading enzymes exhibit attenuated thrombosis at sites of
can bleed after trauma or surgery, spontaneous bleeding is uncom- arterial injury. Polyphosphates released from activated platelets also
mon, and the plasma level of factor XI does not reliably predict the activate factor XII, and may provide another stimulus for contact
propensity for bleeding (see Chapter 137). The capacity of thrombin pathway activation. Mice deficient in factor XII or factor XI form
to feedback and activate platelet-bound factor XI may help to explain small unstable thrombi at sites of arterial or venous damage, suggest-
this phenomenon. It also is possible that platelet-derived factor XI ing that factor XII and factor XI contribute to thrombogenesis (see
may be more important for hemostasis than circulating factor XI. Chapter 137). There is mounting evidence that the same is true in
We cannot ignore the contact pathway, however, because catheters humans. Thus patients with unstable angina have increased plasma
and other blood-contacting medical devices, such as stents or levels of factor XIa which could reflect activation by factor XIIa,
mechanical valves, likely trigger clotting through this mechanism. although activation by thrombin remains a possibility. The best evi-
Factor XII bound to charged or artificial surfaces undergoes a con- dence for the importance of the contact system comes from the results
formational change that results in its activation. Factor XIIa converts of a phase II study that demonstrated that knock down of factor XI
prekallikrein to kallikrein in a reaction accelerated by high-molecular- with an antisense oligonucleotide in patients undergoing elective
weight kininogen, and factor XIIa and kallikrein both feed back knee arthroplasty reduced the risk of postoperative venous thrombo-
to activate additional factor XII. Factor XIIa propagates coagulation embolism to a greater extent than enoxaparin. Furthermore, the
by activating factor XI and generating factor XIa, the predominant thrombi that did form in patients with low levels of factor XI were
activator of factor IX (Fig. 122.5). (See box on Emerging Role of the very small in size, consistent with the role of factor XI in thrombus
Contact Pathway) growth. Therefore the contact system is not only an important driver