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CHAPTER 127 ACQUIRED HEMOPHILIA A

ANTIBODY-MEDIATED DEFINITIONS AND EPIDEMIOLOGY
The incidence of autoantibodies to factor VIII, which is the most com-
COAGULATION FACTOR monly targeted coagulation factor in autoimmunity, is 1.4 per million
people per year. The associated clinical condition is called acquired
2–4
DEFICIENCIES hemophilia A. Approximately 40 to 50 percent of acquired hemophilia
A patients have underlying conditions, including other autoimmune
disorders (e.g., rheumatoid arthritis and systemic lupus erythematosus),
malignancy, pregnancy, or a history consistent with a drug reaction. The
5
Sean R. Stowell, John S. (Pete) Lollar, and Shannon L. Meeks remaining idiopathic cases most commonly occur in elderly patients of
either sex with the median age at diagnosis being in the mid-70s.

SUMMARY MECHANISMS OF ANTIBODY DEVELOPMENT
Even though adaptive immunity provides a unique ability to recognize
Clinically significant autoantibodies to coagulation factors deficiencies are a nearly infinite range of antigenic determinants, mechanisms of immu-
6
uncommon, but can produce life-threatening bleeding and death. The most nologic tolerance exist that reduce the probability of autoimmunity.
commonly targeted coagulation factor in autoimmunity is factor VIII. Acquired Self non-self discrimination provides the key foundation upon which
immune activity can be specifically directed toward potential patho-
hemophilia A, which results from these antibodies, can either be idiopathic gens. However, self non-self discrimination alone does not possess the
6
or associated with older age, other autoimmune disorders, malignancy, the capacity to distinguish innocuous antigens from antigens associated
postpartum period, and the use of drugs such as penicillin and sulfonamides. with a real threat of infection. As a result, an elaborate network of innate
7
Bleeding in acquired hemophilia A is treated with factor VIII bypassing agents. immune factors also exist that recognize potential danger in the form
The underlying autoimmune disorder frequently responds to immunosuppres- of cellular injury or conserved determinants on pathogens themselves,
sive medication. Antiprothrombin antibodies usually are found in patients often referred to as damage-associated molecular patterns (DAMPs)
7,8
with lupus anticoagulant and are associated with bleeding. Antibodies of von and pathogen-associated molecular patterns (PAMPs), respectively.
Willebrand factor are found in patients with type 3 von Willebrand disease in Activation of immune cell function following exposure to PAMPs or
response to infusion of plasma concentrates containing von Willebrand factor. DAMPs provide the necessary signals required for an efficient immuno-
Antibodies to factor V can occur as autoantibodies or as cross-reacting antibo- logic response to foreign antigen. 7–9
The development of anti–factor VIII antibodies following fac-
vine factor V antibodies that develop after exposure to bovine thrombin prod- tor VIII infusion in individuals with hemophilia A provides a classic
ucts that are contaminated with factor V. Pathogenic autoantibodies also have example of the deleterious outcome of alloantibody formation follow-
been described that target thrombin, factor IX, factor XI, factor XIII, protein C, ing exposure to alloantigen. In this scenario, the factor VIII protein is
protein S, and the endothelial cell protein C receptor. foreign to the patients; consequently, central tolerance to the factor VIII
protein does not occur. In contrast, acquired hemophilia results from
loss of previous tolerance to a self antigen. 10–12
For alloantibody development in patients with hemophilia A,
DEFINITION AND HISTORY individual variability in factor VIII levels accounts for some of the
divergent level of tolerance to factor VIII observed. However, some
Antibodies directed against coagulation factors can develop as an individuals with undetectable levels of factor VIII antigen fail to gener-
acquired, autoimmune phenomenon. These “circulating anticoagu- ate factor VIII inhibitors, regardless of factor VIII exposure. Although
lants” or “inhibitors” were recognized as early as 1906 as a cause of an these individuals would not be predicted to be tolerized to factor VIII,
acquired bleeding disorder. The most common coagulation factor tar- 70 to 80 percent of patients with baseline factor VIII levels of less than
1
geted in autoimmunity is factor VIII. The key feature that distinguishes 1 percent do not develop an immune response to repeated dosing
antibody-mediated from other acquired coagulation factor deficiencies, and are considered tolerized. 13–16 For the 20 to 30 percent of patients
such as impaired synthesis (e.g., a result of vitamin K deficiency) or who develop inhibitors there are both genetic and nongenetic risk
increased consumption (e.g., in disseminated intravascular coagula- factors for inhibitor development. Patients with a positive family his-
tion), is the ability of the patient’s plasma to inhibit the coagulation of tory of inhibitors, those who have large factor VIII gene deletions, and
normal plasma. Inhibitors also can develop in response to replacement nonwhites have a higher risk of inhibitor development. 17–20 The non–
therapy in patients with congenital coagulation factor deficiencies as factor VIII genes—interleukin-10, tumor necrosis factor-α, and cyto-
discussed in Chap. 123. toxic T-lymphocyte antigen 4–318 allele—are associated with inhibi-
tor development. 17–20 Nongenetic risk factors, such as infusing factor at
the time of a “danger” signal (e.g., a surgical procedure), intense factor
exposure, and prophylaxis versus no prophylaxis, also are associated
Acronyms and Abbreviations: APC, activated protein C; aPCC, activated proth- with inhibitor development. Patients who receive factor at the time of
16
rombin complex concentrate; aPTT, activated partial thromboplastin time; BU, a “danger” signal may experience sufficient tissue injury to provide the
Bethesda units; CTLA4, cytotoxic T-lymphocyte associated protein 4; DAMP, necessary immune activation through DAMPs. Furthermore, it remains
damage-associated molecular patters; EACH, European Acquired Hemophilia possible that low grade and potentially clinically undetectable infection
Registry; FEIBA, factor eight inhibitor bypasssing agent; PAPP, pathogen-asscoiated may provide low levels of PAMPs that could likewise stimulate anti–fac-
molecular patterns; rVIIa, recombinant activated factor VII. tor VIII antibodies following factor VIII exposure. However, while PAMPs
and/or DAMPs may provide the important immune activation signals, 21,22

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