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Chapter 126 Molecular Basis of Blood Coagulation 1891

factor V is proteolyzed by α-thrombin to the active cofactor factor and vWF levels are elevated as a result of stress, pregnancy, or surgical
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Va. Factor Va functions both as a factor Xa receptor and positive trauma. 105–108
modulator of factor Xa catalytic potential in the prothrombinase
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complex (see Fig. 126.4). Factor Va is proteolytically inactivated by
APC. 62,63 The importance of this regulatory mechanism is demon- The Intrinsic Accessory Pathway Proteins
strated by the “APC resistance” syndrome associated with factor
.
V Leiden 64,65 Individuals with factor V Leiden have a G to A substitution The designation “intrinsic accessory pathway” emerged as the rela-
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at nucleotide 1691 in the factor V gene that results in an Arg →Gln tionship between genetic deficiencies and bleeding phenotypes was
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mutation at the protein level. Factor Va Leiden has normal cofactor established (see Fig. 126.1). Deficiencies of proteins associated with
activity as part of the prothrombinase complex. However, unlike the intrinsic or accessory pathway (factor XII, prekallikrein, and
normal factor Va, factor Va Leiden is more slowly inactivated by APC. high-molecular-weight kininogen [HMWK]) are not ordinarily
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The Arg →Gln mutation hinders the first step in the series of associated with excessive bleeding, even after surgical challenge. 109–111
inactivating cleavages by APC. Cleaved factor Va Leiden retains limited In contrast, deficiencies of the protein components of the extrinsic
cofactor activity and continues to promote thrombin generation. The or primary pathway (prothrombin and factors V, VII, VIII, IX, and
identification, role in coagulation, and overall importance of factor X) can lead to severe bleeding diatheses. 112–116 The physiologic role
V in hemostasis have been described in numerous reviews. 61,67 of the accessory pathway is therefore not clearly understood. 117
Although the intrinsic pathway proteins have no defined role in
Factor VIII normal hemostasis, these accessory pathway factors are thought to
The soluble procofactor factor VIII, or antihemophilic factor (see Fig. play a key role in disseminated intravascular coagulation associated
126.5B), circulates in plasma in complex with the large multimeric with the systemic inflammatory response syndrome 118,119 and in the
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protein vWF. vWF acts to regulate the plasma concentration of promotion of thrombus stability, 117,120,121 and may be a new target to
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factor VIII. Factor VIII interaction with vWF requires the NH 2- and control pathologic coagulation. Also, the accessory pathway is
COOH-termini of the factor VIII light chain (A3, C1, and C2 important in cardiopulmonary bypass because of contact between
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domains), although a specific vWF binding site has been identified blood components and synthetic surfaces. Recent evidence suggests
at residues 1673–1684 on the light chain. 68–71 Factor VIII is activated that biologic activation of the contact pathway system may be
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by thrombin cleavage at three sites (Arg , Arg , Arg 1689 ) to generate accomplished through assembly of these proteins on endothelial cell
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the heterotrimeric cofactor factor VIIIa. The vWF binding site is membranes and that prekallikrein is activated by an endothelial cell
removed from the factor VIII protein by thrombin cleavage at Arg 1689 . membrane cysteine protease rather than by factor XII. 123,124 Extracel-
After forming, vWF–free factor VIIIa forms a complex with the serine lular RNA derived from damaged or necrotic cells has also been
2+
protease factor IXa, Ca , and a membrane (provided by platelets), found to participate in the activation of proteases of the contact
resulting in the intrinsic tenase (see Fig. 126.4). Factor VIIIa function pathway by providing a procoagulant cofactor template for factor
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is downregulated by the relatively rapid dissociation of the noncova- XII- or XI-induced contact activation. Polyphosphates, linear
lently associated A2 subunit, which is produced by the cleavages inorganic polymers of 60–100 phosphate residues, released from
required for activation. Factor VIII is homologous (40% identity) to platelets have also been shown to activate fXII. 126
the procofactor factor V. 73 In principle, factor XI represents an intersection point for the two
Deficiency of factor VIII, or hemophilia A, is a well-characterized pathways. Individuals with factor XI deficiency (hemophilia C) have
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bleeding disorder linked to the X chromosome. Hemophilia A a variable bleeding phenotype upon surgical challenge, 127,128 therefore
therefore occurs almost exclusively in males at a frequency of 1 in establishing an essential role for factor XI in hemostasis. During the
5000 to 1 in 10,000 individuals. 75 coagulation process, factor XIa formation appears to be catalyzed by
thrombin as part of a positive-feedback loop stemming from throm-
von Willebrand Factor bin generation. Factor XIa then functions in the propagation phase
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vWF has several key roles in coagulation. It is synthesized in endo- of thrombin generation in association with the primary pathway by
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thelial cells and also contained in the α-granules of human platelets. activation of factor IX. 130
vWF is a large adhesive GP that circulates in plasma as a heteroge- Three proteins, factor XII, prekallikrein, and HMWK, are
neous mixture of disulfide-linked multimers that range in size from required for activity of the intrinsic or accessory pathway. Factor XII
dimers (M r = 600,000) to extremely large multimers of more than and prekallikrein are zymogens that are activated to generate serine
20 million kDa. vWF has binding sites for factor VIII, heparin, proteases, and HMWK is a nonenzymatic procofactor (Fig. 126.6).
collagen, platelet GPIb, and platelet GPIIb–IIIa. 77–90 vWF acts as the The activation of this pathway in vitro is accomplished when factor
bridge between platelets to promote platelet aggregation. The primary XII autoactivates to factor XIIa upon exposure to foreign surfaces,
platelet binding site for vWF is the GPIb–IX–V receptor complex. including kaolin, dextran sulfate, and sulfatides. 131–133 The substrates
GPIb–IX–V is an active receptor on unstimulated platelets and serves for factor XIIa, prekallikrein, and factor XI exist in noncovalent
to promote platelet aggregation and adhesion to vWF in the absence complex with HMWK and become activated to kallikrein and factor
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of platelet activation. 91 XIa, respectively. Positive-feedback loops exist in which kallikrein
vWF is a structural protein and is part of the subendothelial cleaves HMWK, thereby releasing bradykinin and allowing more
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matrix. Endothelial cells secrete vWF multimers, which are larger prekallikrein and factor XI to associate and activate. This pathway
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than those found circulating in plasma. The function of these large is also negatively regulated by the cleavage of HMWK by factor
multimeric forms of vWF is to bind to and agglutinate blood platelets XIa. 136
under high shear conditions. These large multimers of vWF are
degraded by a specific metalloprotease called a disintegrin and metal-
loproteinase with a thrombospondin type 1 motif, member 13 Proteinase Inhibitors
(ADAMTS)-13. 93–95 In familial and acquired thrombotic thrombo-
cytopenic purpura, ultra-large vWF multimers are correlated with Proteinases, enzymes that hydrolyze peptide bonds, are found in a
defective ADAMTS-13 activity. 96 wide array of biologic systems, including the blood coagulation
ABO blood type has a significant influence on vWF levels, with process (clot formation and fibrinolysis), digestive system, apoptotic
individuals of types A, B, or AB blood having much higher levels of cascades, and the immune system. To keep these systems in balance
vWF than those with type O blood. 97,98 vWF is also known for its between activation and inhibition, a complex system of proteinase
role in ristocetin-induced platelet agglutination, 99,100 which is the inhibitors has evolved. In blood, proteinase inhibitors constitute a
basis of clinical assays for von Willebrand disease, a fairly common significant percentage of circulating proteins. In general, proteinases
disorder that is estimated to occur in 1%–2% of the general popula- that activate the coagulation and fibrinolytic cascades have highly
tion (see Chapter 138). 101–104 vWF is also an acute-phase reactant, defined substrate specificities. Coagulation is kept in check through