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2186 Part XII: Hemostasis and Thrombosis Chapter 127: Antibody-mediated Coagulation Factor Deficiencies 2187

Although acquired inhibitors may remit spontaneously, fatal cross-react with human thrombin, factor V, or prothrombin. Usually,
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bleeding may occur up to several months after the initial diagnosis, even these antibodies are subclinical. However, mild to life-threatening
in patients who present with mild bleeding. Therefore, immunosuppres- hemorrhage can occur, especially if the titer of anti–human factor V
sive therapy at the time of diagnosis to eradicate the inhibitor is rec- antibodies is high. The risk of bleeding is higher in patients who receive
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ommended. A variety of immunosuppressive agents have been used, bovine thrombin products more than once because of the development
including cyclophosphamide, azathioprine, cyclosporine, intravenous of a secondary immune response.
immunoglobulin, and rituximab. Immune tolerance induction using There have been no clinical trials comparing the safety and effi-
human factor VIII similar to what is done for patients with congenital cacy of fibrin sealants to stand-alone thrombin products. Because fibrin
hemophilia A and inhibitors has been used successfully. Additionally, sealants are composed mainly of human proteins, they may be less
plasmapheresis and immunoadsorption of the inhibitory antibody have immunogenic. However, anti–factor V antibodies have been reported
been used. in a patient receiving fibrin sealant. There currently is no stand-alone
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First-line immunosuppressive regimens at many centers consist human thrombin product. It seems likely that the development of
of glucocorticoids alone or glucocorticoids combined with cyclophos- highly purified plasma-derived or recombinant products containing
phamide. No appropriately powered randomized studies have been human thrombin in the presence or absence of human fibrinogen would
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performed, so the information available is from a single small random- decrease the incidence of antithrombin and anti–factor V antibodies. 70
ized study, case reports, national surveys, and large registry data. The Autoantibodies to thrombin are rare. However, the mechanisms
single randomized trial of 31 patients comparing prednisone and cyclo- of action of antithrombin antibodies have been studied extensively
phosphamide showed no difference in the treatment arms. A national because of the wealth of information about thrombin structure and
registry study also showed no difference with 76 percent of patients function. 74–77 In contrast, approximately half of the 105 cases of inhibi-
achieving complete remission in the steroid arm and 78 percent in the tory anti–factor V antibodies reported and reviewed between 1955 and
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steroids plus cytotoxic agent arm. The EACH2 Registry has the largest 1997 appeared to be autoantibodies not associated with the exposure
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reported experience with 331 patients and reported a higher rate of sta- to bovine thrombin products. β-Lactam antibiotics also are associated
ble complete remission at 70 percent for patients treated with steroids with anti–factor V autoantibodies and may partly explain the increased
and cyclophosphamide compared with 48 percent for steroids alone incidence with surgery. In approximately 20 percent of cases of autoan-
and 59 percent for rituximab containing regimens. Extensive analysis tibody formation, no underlying disease was identified. Anti–factor V
to control for potential confounding factors in this non-randomized autoantibodies have been identified rarely in patients with autoimmune
study confirmed that stable complete remission was more likely with a diseases, solid tumors, and monoclonal gammopathies. In addition
steroid and cyclophosphamide than steroids alone (odds ratio of 3.25). to autoantibody formation, alloantibodies to factor V have developed
The median time to remission was 5 weeks in patients treated with ste- in patients with severe factor V deficiency in response to replacement
roids alone or steroids and cyclophosphamide and 10 weeks in patients therapy with fresh-frozen plasma.
treated with rituximab. There have been no studies that have shown Patients with inhibitory antibodies to factor V have prolonged
a difference in long-term outcomes including survival and sustained prothrombin and aPTT, low factor V levels, and a normal thrombin
remission. 57,67 time. The diagnosis of a factor V inhibitor is based on the specific loss of
The rarity of this disease, the severity of bleeding at onset, and factor V coagulant activity when patient and normal plasma are mixed in
the delay in diagnosis of these patients has all contributed to the lack a coagulation assay. The antibody titer can be defined as in the factor VIII
of controlled trials. Given the lack of controlled trial clinical manage- Bethesda assay as the dilution of test plasma that produces 50 percent
ment decisions are guided from the limited data available and clinical inhibition of factor V activity.
judgment. Not all patients with factor V inhibitors have hemorrhagic manifes-
tations. Factor V inhibitors anecdotally produce a less serious bleeding
disorder than factor VIII inhibitors. The relationship between inhibitor
ACQUIRED ANTIBODIES TO OTHER titer and bleeding has not been studied. The reported incidence of bleed-
COAGULATION FACTORS ing has been higher in patients with autoantibodies to factor V com-
pared to anti–factor V antibodies in patients receiving bovine thrombin.
ANTI–FACTOR V AND ANTITHROMBIN However, this may reflect a bias resulting from the reason the patient
ANTIBODIES sought medical attention.
Factor V contains an A1-A2-B-A3-C1-C2 domain structure that
Thrombin and factor V inhibitors are discussed together because of is homologous to factor VIII. Also, like factor VIII, the N-terminal half
their frequent coexistence in immune responses to commercial prod- of the factor V C2 domain contains a phospholipid-binding site that is
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ucts that contain thrombin. Thrombin products have been used widely necessary for normal procoagulant function and is targeted by factor
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in surgical and endoscopic procedures. It has been estimated that more V inhibitors. 80,81
than 500,000 patients are treated annually with products containing
thrombin. Thrombin is used either alone or as a component of fibrin
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sealants, which consist of fibrinogen and thrombin preparations that are ANTIPROTHROMBIN ANTIBODIES
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mixed together at the wound site to form a topical fibrin clot. Addi- Antiprothrombin antibodies are most commonly associated with the
tionally, factor XIII sometimes is added to crosslink and stabilize the antiphospholipid syndrome. The antiphospholipid syndrome is caused
clot. by lupus anticoagulants, which are defined as antibodies that produce
Fibrin sealants contain thrombin and fibrinogen derived from phospholipid-dependent prolongation of in vitro coagulation assays.
human plasma, whereas stand-alone thrombin products are prepared Anionic phospholipids participate as cofactors for the lupus antico-
from bovine plasma. Both types of products are heavily contaminated agulant binding to protein antigens, primarily β -glycoprotein I and
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with other plasma proteins, including factor V and prothrombin. 70,71 prothrombin. The antibody–antigen complexes compete for the bind-
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Almost all patients exposed to bovine proteins develop a detectable ing of coagulation factors to the phospholipid present in coagulation
immune response. In half of these patients antibovine antibodies assays and produce the lupus anticoagulant phenomenon.

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