Elsevier

Autoimmunity Reviews

Volume 13, Issue 1, January 2014, Pages 40-48
Autoimmunity Reviews

Review
Autoantibodies to coagulation factors: From pathophysiology to diagnosis and therapy

https://doi.org/10.1016/j.autrev.2013.08.001Get rights and content

Abstract

Autoantibodies may develop against coagulation factors altering their function or promoting their rapid clearance. In non-congenitally deficient patients, they are usually in association with autoimmune diseases, malignancies, pregnancy or advanced age. The possible development of coagulation factor autoantibodies should be considered when a patient presents with bleeding symptoms without any prior bleeding diathesis. The most common disorder associated with coagulation factor autoantibodies is acquired factor VIII deficiency, which is characterized by hemorrhages involving soft tissues, muscles and skin; hemarthroses are less frequent than in the inherited form. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Autoantibodies to the other coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions.

The diagnostic approach begins with global coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). In case of prolonged times, mixing studies (typically using normal plasma in a 1:1 proportion) should be performed. Specific factor and inhibitor assays, assessment of lupus anticoagulant and eventually enzyme immunoassays for specific anti-factor antibodies complete the evaluation. A prompt diagnosis of specific coagulation factor inhibitors is mandatory for starting an appropriate treatment aimed at overcoming the deficient factor, in case of bleeding, and, if possible, at the suppression of the autoantibody's production.

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

  • 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.

  • In the presence of bleeding in patients with a negative personal and familiar hemorrhagic history, an underlying coagulation

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