Acquired dysfibrinogenemia caused by monoclonal production of immunoglobulin light chain
Molecular Pathology Laboratory, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.Haematologica (Impact Factor: 5.81). 12/2007; 92(11):e111-7. DOI: 10.3324/haematol.11837
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 lambda 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 lambda chain lost its anti-fibrinogen activity, apparently due to dimerization. The 63-year-old patient acquired dysfibrinogenemia from a monoclonal production of lambda 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.
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ABSTRACT: Hereditary dysfibrinogenemia is a rare clotting disorder due to a structural defect in the fibrinogen molecule that results in a tendency for bleeding and thrombosis, as well as obstetric complications. We describe the laboratory results and clinical manifestations for 50 patients with a diagnosis of dysfibrinogenemia. Various different laboratory measurements of fibrinogen were performed on samples from these patients, including fibrinogen (Clauss), heat fibrinogen precipitation according to Schulz and immunological fibrinogen. Fifty patients were found with dysfibrinogenemia (52% female; median age 52, range 9-89 years). The fibrinogen level according to Clauss was low, with a median of 51 mg/dL (range 15-86 mg/dL; normal range 150-450 mg/dL). Determination of other fibrinogen levels revealed normal results: heat fibrinogen precipitation according to Schulz, 240 mg/dL; and immunological fibrinogen, 244 mg/dL. The median reptilase time was longer than normal, at 55 s (normal 20 s). Some 50% of the patients reported a distinct bleeding tendency, mostly a tendency for hematoma (60%) and secondary bleeding (44%). Thirteen patients had thrombotic events, of which 54% were located arterially. Some 12% of the patients reported a tendency for bleeding and for thrombosis, whereas 19% had miscarriages, sometimes recurrent. We found that functional fibrinogen levels (Clauss) were generally lower in patients with bleeding manifestations, (43 vs. 57 mg/dL in other patients).Laboratoriums Medizin 11/2008; 32(6):401-405. DOI:10.1515/JLM.2008.059 · 0.21 Impact Factor
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ABSTRACT: Abnormal coagulation properties indicative of a dysfibrinogen were found in the plasma of a 72-year-old male with multiple myeloma (IgGkappa, stage IIIA). The patient had high paraprotein concentration (85.75 g/l) and prolonged thrombin time (76.8 s), activated partial thromboplastin time (39.5 s), prothrombin time (23.5 s) and reptilase time (72.0 s). The fibrinogen level was increased. The fibrin polymerization induced by both thrombin and reptilase was impaired. Scanning electron microscopy revealed abnormal clot morphology. After six months of treatment, the paraprotein level decreased (19.48 g/l) and coagulation normalized as well as fibrin polymerization and fibrin clot morphology. It was found that the paraprotein interacts with the gamma-chain of fibrinogen. Acquired dysfibrinogenemia associated with multiple myeloma was diagnosed in the 72-year-old patient.Acta Haematologica 11/2008; 120(2):75-81. DOI:10.1159/000160182 · 1.12 Impact Factor
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ABSTRACT: Microparticles are small membrane vesicles released from activated cells and are associated with thrombosis and inflammation. Microparticle contain a unique subset of surface protein derived form the parent cell and may be responsible for their diverse biological functions. To identify these proteins, juvenile baboons (Papio anubis, n = 4) underwent iliac vein thrombosis with 6-hour balloon occlusion. Plasma samples were taken at baselines and at 2 days postthrombosis for microparticle analysis. Microparticles were extracted from platelet-poor plasma, digest separately with trypsin and tagged using isobaric tagging for relative and absolute quantitation reagents. The digests were subjected to 2-dimensional liquid chromatographic separation followed by matrix-assisted laser desorption/ionization tandem mass spectrometry. Peak lists were generated and searched against all primate sequences. For protein identity, a minimum of 2 peptides at 95% confidence interval was required. Later, isobaric tagging for relative and absolute quantitation ratios were generated comparing relative protein level of day 2 to baseline. The proteomic analysis was performed twice for each blood sample, totaling 8 experiments. Proteins were considered elevated of depressed if the isobaris tagging for relative and absolute quantitation ratio deviated by 20% changes from normal and a P value less than .05. Significantly, 7 proteins were differentially expressed on day 2 compared to baseline, and appeared in at least 3 animals and regulated in at least 4 experiment. Among these 7 proteins, upregulated proteins include various forms of fibrinogen and alpha-1-antichymotrypsin and downregulated proteins include immunoglobulins. These proteins influence thrombosis and inflammation through hemostatic plug formation (fibrinogen), inhibiting neutrophil adhesion (alpha-1-antichymoptrypsin), and immunoregulation (immunoglobulins). Further studies are needed to confirm the mechanistic role of these proteins in the pathogenesis of venous thrombosis.Clinical and Applied Thrombosis/Hemostasis 12/2008; 15(2):201-8. DOI:10.1177/1076029608326753 · 2.39 Impact Factor
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