ReviewAutoantibodies to coagulation factors: From pathophysiology to diagnosis and therapy
Introduction
The coagulation cascade consists in a series of proteolytic reactions by means of serine proteases generated from zymogens (Fig. 1). The final event is the formation of a fibrin clot that can stop the leakage of blood from a damaged vessel [1]. Conventionally, these reactions have been divided in three pathways: extrinsic (tissue factor and factor VII), intrinsic (factors VIII, IX and XI), and common (factors II, V and X) pathways. The contact activation pathway (factor XII, prekallikrein and high molecular weight kininogen) seems to be more involved in the inflammatory process and has a minor role in initiating clot formation, as supported by the observation that patients with severe deficiencies of these factors do not develop a bleeding disorder [1].
Autoantibodies against coagulation factors are pathologically acquired circulating immunoglobulins (Igs) predominantly of the isotype G (IgG), particularly the IgG4 subclass [2]. They partially or completely neutralize the activation or function or promote rapid clearance of a specific clotting factor from the blood [2]. Coagulation factor autoantibodies are uncommon in non-congenitally deficient patients, however when present, they are in association with autoimmune diseases, lymphoid malignancies, pregnancy, as well as advanced age. They are rare in the pediatric population, except in patients with a severe congenital factor deficiency after factor replacement [3].
Autoantibodies to coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions. Coagulation factor autoantibodies, which are specifically directed to a single clotting factor, are different from another category of naturally occurring anticoagulants like lupus anticoagulant, the anti-phospholipid antibodies, which interfere with different coagulation reactions [4]. Anti-phospholipid antibodies are not associated with bleeding, but with a prothrombotic diathesis with arterial or venous thrombosis and/or recurrent pregnancy loss [5], [6], [7] and will not be covered here.
In this review, we will focus on the pathophysiology of autoantibodies directed to single coagulation factors and the related clinical entities, trying to provide a simple approach for diagnosis and therapy.
Section snippets
Pathophysiology and clinical manifestations
Autoantibodies against all of the coagulation factors have been described, however those directed against factor VIII are the most commonly found [8], [9]. They are different from inhibitors occurring in patients with congenital bleeding disorders, such as hemophilia A, after replacement therapy. The latter are usually called “alloantibodies”, however, in most cases they are technically “isoantibodies”, which are defined as antibodies that react with antigens of another member of the same
Laboratory tests
The laboratory identification of factor inhibitors requires a careful and systematic approach to rule out potential other causes of prolonged screening tests, most commonly the activated partial thromboplastin time (aPTT), and, less frequently, the prothrombin time (PT). After these tests as initial screening, coagulation factor inhibitor studies must be undertaken [67]. Table 1 reports the main laboratory tests useful for detection and identification of coagulation factor inhibitors. Fig. 2
Clinical approach
When a patient presents with bleeding symptoms without any prior bleeding diathesis or family history of coagulation defects, the possible development of coagulation factor autoantibodies should be considered [2], [9], [68].
Acquired factor VIII deficiency is the most common disorder, and is characterized by hemorrhages involving soft tissues, muscle and skin; hemarthroses are less frequent than in the inherited form [16]. Acquired von Willebrand syndrome presents with epistaxis,
Therapeutic options
Therapeutic strategies in patients with coagulation factor inhibitors are aimed to arrest the bleeding, and to eradicate the inhibitor.
Whenever possible, the underlying disorder should be treated and the responsible drug removed. General measures such as rest, avoidance of any surgical intervention or invasive diagnostic procedure, discontinuation of drugs with known inhibitory effect on coagulation system and application of antifibrinolytic agents can further help hemostasis.
Moreover, patients
Take-home messages
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Bleeding disorders due to autoantibodies against coagulation factors are rare, however among them, the most frequent are related to anti-factor VIII autoantibodies. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Antibodies to other coagulation factors are very rare and described only in scattered reports.
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In the presence of bleeding in patients with a negative personal and familiar hemorrhagic history, an underlying coagulation
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