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2184 Part XII: Hemostasis and Thrombosis Chapter 127: Antibody-mediated Coagulation Factor Deficiencies 2185

several studies using animal models suggest that significant factor antibodies in both congenital and acquired hemophilia A inhibitor are
VIII antibody development can occur in the absence of known tissue primarily directed to the A2 and C2 domains, although antibodies to
injury or DAMP exposure. Consistent with this, immune activation all domains have been described. 33–35 The similarity in the properties of
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can occur in the apparent absence of DAMPs or PAMPs toward sev- antibodies in congenital and acquired hemophilia, which represent very
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eral model antigens. Unique B-cell populations, especially those in the different immunologic settings, suggests that intrinsic structural features
spleen, can rapidly respond to bloodborne antigens in the absence of in the factor VIII molecule are an important determinant driving the
any identifiable PAMPs or tissue injury, suggesting that these cells may immune response. Epitope spreading from a single “problem” epitope,
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be uniquely poised to respond to factor VIII. Consistent with this, in which has been implicated in some autoantibody phenomena, does
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experimental models, splenectomy can significantly inhibit factor VIII not appear to be a property of factor VIII inhibitors because anti–C2
inhibitor development following factor VIII exposure, 26,27 suggesting antibodies can occur in the absence of anti–A2 antibodies and vice versa.
that several of these unique B-cell populations may be involved in the The only known biologic function of factor VIII is to become
development of factor VIII antibodies irrespective of DAMP or PAMP proteolytically activated and participate as a cofactor for factor IXa
exposure. 25,26 during intrinsic pathway factor X activation on phospholipid mem-
Although examples of antigens inducing B-cell activation in the branes. Theoretically, antibodies could inhibit factor VIII procoagu-
absence of known DAMPs or PAMPs exist, most of these antigens require lant function in several ways, including blocking the binding of factor
crosslinking of cell-surface B-cell receptors for efficient activation and VIIIa to factor IXa, factor X, or phospholipid, or by interfering with the
therefore reflect highly repetitive antigenic structures. In contrast, fac- proteolytic activation of factor VIII. Some anti-A2 antibodies map to
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tor VIII represents a soluble antigen with little inherent predicted cross- a region bounded by Arg484-Ile508 and inhibit activated factor VIII
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linking ability. Most soluble antigen of this type actually induce tolerance by blocking its ability to bind factor X. Anti-C2 antibodies bind to the
following injection, likely because of the inability of soluble monovalent NH -terminal half of the C2 domain. Anti-C2 antibodies have been
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antigens to adequately crosslink and thereby stimulate B-cell recep- identified that inhibit the binding of activated factor VIII to phospho-
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tors. Although factor VIII can exist in a soluble, monovalent form, it lipid membranes, which is critical for its interaction with the platelet
remains possible that factor VIII may form complexes with higher- surfaces. However, the C2 domain also apparently contributes to the
molecular-weight species and thus form a network of factor VIII anti- binding of factor VIII to its activators, thrombin and factor Xa. 41–43 Con-
gens that may serve as a suitable substrate for efficient B-cell receptor sistent with this, anti–C2 inhibitors have been identified that block fac-
crosslinking and subsequent activation. Consistent with this, induction tor VIII activation. 41,44
of tolerance to factor VIII by exposure to high levels of factor VIII may Factor VIII inhibitors also have been identified in approximately
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partially reflect a saturation of sites for factor VIII complex formation, 20 percent of normal healthy donors. These inhibitors inhibit factor
which may, in turn, result in B-cell exposure to high levels of soluble, VIII activity in pooled normal plasma, but not autologous plasma,
monovalent factor VIII. However, if this occurs, studies suggest that it indicating that they are not autoantibodies, but rather alloantibodies
likely takes place independent of interactions with von Willebrand fac- directed against an unidentified polymorphism. Anti–factor VIII IgG
tor, the primary binding partner of factor VIII, or its own coagulant also has been identified in all normal plasmas tested by affinity chro-
activity. Clearly, there is much more to learn regarding the immuno- matography on immobilized factor VIII. The increased sensitivity of
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logic factors responsible for factor VIII inhibitor development. the method is a consequence of its ability to resolve anti–factor VIII
In contrast to generating alloantibodies following factor VIII infu- antibodies from anti–anti–factor VIII idiotypic antibodies that also are
sion, some patients generate autoantibodies against factor VIII, which can present. Idiotypic regulation has been proposed as a mechanism for
result in acquired factor VIII deficiency. As coagulation typically occurs controlling autoantibody activity in vivo. 47
at sites of inflammation and injury where DAMPs presumably are gener-
ated, tolerance to factor VIII may unfortunately be lost in these settings.
Additionally, nonproteolytic and proteolytic degradation of coagulation CLINICAL FEATURES
proteins potentially could present neoepitopes. However, the fact that the Acquired hemophilia A patients usually present with spontaneous bleed-
development of acquired factor VIII deficiency is rare (1.4 per million ing, which often is severe and life- or limb-threatening, although large
population) provides a testimony to the ability of the immune system to cohort studies have shown that approximately 30 percent of patients do
2,48
discriminate efficiently between infectious non-self from noninfectious not require hemostatic management. Patients with acquired hemo-
self. Essentially, nothing is known about the breakdown of tolerance in philia are more likely to have a severe bleeding diathesis than congenital
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patients that develop autoantibodies to coagulation factors. hemophilia A inhibitor patients. Additionally, in contrast to patients
with congenital hemophilia A, hemarthrosis in these patients is rare. The
reasons for these differences is puzzling, especially in light of the fact that
MOLECULAR PATHOLOGY the properties of factor VIII inhibitors in the two patient populations is
Factor VIII inhibitors in congenital and acquired hemophilia nearly similar. As noted above, inhibitors can block factor VIII function in sev-
always consist of a polyclonal immunoglobulin (Ig) G population. eral ways. Conceivably, unidentified mechanistic differences in inhibitor
Although IgG accounts for only 5 percent of the total IgG in normal action account for the difference in clinical severity. Factor VIII inhib-
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plasma, it usually is a major, but not the sole, component of the anti– itors sometimes resolve spontaneously. However, it is not possible to
factor VIII antibody population. IgG antibodies do not fix comple- predict in which subset of patients this will occur.
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ment, which has been cited as a reason that immune complex disease
is not observed in factor VIII inhibitor patients. However, it is more LABORATORY FEATURES AND DIFFERENTIAL
likely that factor VIII simply is not present in sufficient quantity to form
enough immune complex deposition to mediate tissue damage. DIAGNOSIS
Factor VIII contains a sequence of domains designated A1-A2- The new onset of an acquired bleeding disorder should immediately
B-ap-A3-C1-C2 (Chap. 123). During the activation of factor VIII lead to screening tests that include an activated partial thromboplastin
by thrombin, the B and ap domains are released, producing an A1/ time (aPTT), a prothrombin time, and a platelet count. Patients with
A2/A3-C1-C2 activated factor VIII heterotrimer. Anti–factor VIII acquired hemophilia A have a prolonged aPTT resulting from decreased
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Kaushansky_chapter 127_p2183-2190.indd 2184 17/09/15 3:43 pm