Acquired dysfibrinogenemia: monoclonal λ-type IgA binding to fibrinogen caused lower functional plasma fibrinogen level and abnormal clot formation

Abstract

Background: We reported a case of acquired dysfibrinogenemia with monoclonal gammopathy of undetermined significance presenting λ-type IgA M protein. The patient showed lower functional (0.38 g/dL) and normal immunological fibrinogen (3.24 g/dL).To examine the cause of the false lower value of fibrinogen, we performed experiments using the patient's purified fibrinogen and IgA. Methods: Fibrinogen was purified from the patient's plasma, and IgA was purified from patient's plasma or serum by immunoaffinity chromatography. We performed thrombincatalyzed fibrin polymerization, scanning electron microscopy (SEM), immunoblotting analysis, and enzyme-linked immunosorbent assays (ELISAs).Results: Fibrin polymerization in the patient's plasma was markedly reduced, and SEM showed no fiber bundles or sponge-like structures. Purified IgA did not influence polymerization, whereas immunoprecipitated plasma with an anti-IgA (α-chain) antibody indicated normalization of polymerization and clot structure. Western blotting analysis revealed the presence of monoclonal λ-type IgA-bound fibrinogen, and the proportion was significantly higher than normal control plasma using ELISA. Conclusion: Our results suggested that IgA M protein-bound fibrinogen is not normally converted into fibrin, and instead finally forms an aberrantly structured fragile clot. The 3 patient's reduced plasma fibrinogen level was caused by the presence of IgA M proteinbound fibrinogen and not by IgA M protein alone.

Diagnosis and classification of hereditary fibrinogen disorders

“…Before starting investigations of HFD, it is important to rule out an acquired fibrinogen disorder. Liver disease, drugs and cancer, the most common causes, can affect the synthesis, the secretion, or the proteolysis of fibrinogen resulting in decreased levels of fibrinogen activity 9,10 . The familial history is also crucial, often helping to distinguish between a hereditary and acquired fibrinogen disorder.…”

Rediscovering hemostasis abnormalities in multiple myeloma: The new era

“…The underlying mechanisms include: (1) the high level of paraproteins in plasma induces an increase in plasma viscosity to alter fibrin polymerization; (2) paraproteins can be used as anti-fibrinogen antibodies to bind to fibrinogen, and (3) paraproteins may bind to fibrinogen through non-specific reactions [ [26] , [27] , [28] ]. Interestingly, paraproteins do not affect the interaction between thrombin and fibrinogen and the release of fibrin peptide, but they interact with fibrinogen γ chain, changing the formation and network structure of fibrils, reducing the mass to length ratio of fibrin fibers and increasing the hardness of fibrin gel [ 27 , 28 ]. They also reduce the lateral gathered to form gelatinous fragile clots, resulting in bleeding [ 27 , 28 ].…”

“…Interestingly, paraproteins do not affect the interaction between thrombin and fibrinogen and the release of fibrin peptide, but they interact with fibrinogen γ chain, changing the formation and network structure of fibrils, reducing the mass to length ratio of fibrin fibers and increasing the hardness of fibrin gel [ 27 , 28 ]. They also reduce the lateral gathered to form gelatinous fragile clots, resulting in bleeding [ 27 , 28 ].…”