Acquired dysfibrinogenemia caused by monoclonal production of immunoglobulin λ light chain

Abstract

Disorders of fibrinogen are usually caused by genetic mutations that result in low protein levels (hypofibrinogenemia) or an abnormal molecule (dysfibrinogenemia). However, environmental and plasma factors can have an acquired effect on its expression or function. For example, antibodies can bind fibrinogen and/or fibrin to interfere with polymerization and inhibit coagulation. The objective here was to determine the cause of dysfibrinogenemia in a 63-year-old man. Despite a low functional fibrinogen concentration and prolonged thrombin time, no inherited fibrinogen abnormality could be detected after extensive protein analysis and gene sequencing. Thus, electrophoresis methods and fibrinogen binding studies were used to establish the cause of the acquired dysfibrinogenemia. An immunoglobulin λ light chain was found to bind fibrinogen as a monomer. It had no significant effect on fibrinopeptide release, but caused substantial defects in all other stages of thrombin-catalyzed fibrin polymerization. Binding to fibrinogen also seemed to prevent the light chain from being filtered through the kidneys, causing only low levels of it in the urine. Once in the urine, the λ chain lost its anti-fibrinogen activity, apparently due to dimerization. The 63-year-old patient acquired dysfibrinogenemia from a monoclonal production of λ light chain that bound and inhibited the function of fibrinogen. At age 64.5 he was diagnosed with monoclonal gammopathy of undetermined significance, explaining the abnormal immunoglobulin chain production. This case was particularly unusual in that the inhibition of fibrin polymerization was caused by a single immunoglobulin light chain, rather than by a whole antibody molecule.

Fibrinogen is synthesized in hepatocytes as a 340 kDa disulfide-bonded dimer of three pairs of polypeptide chains; (Aα, Bβ, γ)₂. Once secreted into the circulation, it is intimately involved in health and disease through its pivotal roles in blood coagulation, platelet aggregation and wound healing, and is maintained at a plasma concentration of 1.5–4.0 mg/mL. In the final stages of the coagulation cascade, thrombin activates fibrinogen by cleaving fibrinopeptides from the Aα and Bβ chains. Exposure of the A polymerization site is sufficient to initiate fibrin polymerization, whereby the new a chain N-terminus docks with a constitutively exposed cavity in the C-terminal domain of the γ chain. The resulting protofibrils aggregate to form the matrix of a blood clot and become stabilized by factor XIIIa-mediated covalent cross-linking. The fibrin matrix preserves the integrity of the hemovascular system by restricting blood loss and promotes wound healing by providing a scaffold for the migration and adhesion of other proteins and cells.1

Most disorders of fibrinogen are caused by genetic mutations that result in low levels of normal protein (hypofibrinogenemia) or normal levels of an abnormal molecule (dysfibrinogenemia). However, acquired disorders highlight a number of environmental and plasma factors that can have an effect on fibrinogen expression and function. Acquired abnormalities of fibrinogen occur in patients with a number of underlying diseases. For example, acquired dysfibrinogenemia associated with liver disease is caused by increased sialylation of the Bβ and γ chains, with the increased negative charge causing a decrease in polymerization rate.2 Diseases that cause increased immunoglobulin production (myeloma) or autoantibody activation (systemic lupus erythematosus (SLE)) have also been associated with abnormal fibrin polymerization, but this is not usually caused by specific activity against fibrinogen.3,4 That said, two patients with multiple myeloma5,6 and three patients with SLE7,8 have been reported to have prolonged thrombin times caused by anti-fibrinogen autoantibodies. Other disease states associated with autoantibodies toward fibrinogen include renal insufficiency,9 migratory thrombophlebitis,10 sarcoidosis with isoniazid therapy,11 chronic liver disease12 and Down’s syndrome.13 There are also examples of anti-fibrinogen antibodies developing spontaneously for no determined reason.14–16 Anti-fibrinogen alloantibodies are equally rare, but there have been reports of their appearance in afibrinogenemic patients who have received fibrinogen replacement therapy.17–19 Another patient developed alloantibodies against fibrinogen, thrombin and factor V after receiving bovine topical thrombin as a hemostatic agent.20 Non-clinically relevant antibodies also develop toward fibrinogen degradation products in most normal individuals and during pregnancy. These may provide a bridge between the hemostatic and immune systems to control the pathogenic actions of fibrinogen fragments.

Acquired antibodies to fibrinogen and/or fibrin can interfere with fibrinopeptide release, fibrin polymerization or factor XIIIa-mediated cross-linking and usually create an abnormal coagulation profile, although there has been no consistent correlation with bleeding. They are usually whole immunoglobulin molecules and are rare enough to merit case reports. The case presented here was particularly unusual in that the inhibition of fibrin polymerization was caused by a single immunoglobulin λ light chain, rather than by a whole antibody molecule. There has only been one previous report of a light chain binding and inhibiting the function of fibrinogen.